JP2021534242A - Particles containing colorants and how to use them - Google Patents

Abstract

The present disclosure relates to compositions designed to be administered intradermally to a subject to treat unpigmented skin or to create a temporary tattoo. The composition comprises particles having a polymer shell and a core containing a colorant. The particles are present in the carrier solution at a cosmetically effective concentration to delay bioabsorption and / or biodegradation of the colorant in the subject's skin. Bioabsorption and / or biodegradation of particles causes the tattoo to fade until it is no longer visible.

Description

Cross-reference of related applications
[0001] This application claims the priority of US Provisional Patent Application No. 62 / 717,584, filed August 10, 2018, the entire contents of which are incorporated herein by reference.

[0002] Evidence of skin decoration dates back to prehistoric times and was once used to identify identities (eg, spouse or military rank), to identify affiliations, and for aesthetic purposes. It had been. Takimi has also been used therapeutically to treat skin conditions such as depigmentation and hyperpigmentation caused by vitiligo, skin grafts, and port wine nevus.

[0003] Tattoos are typically applied by applying ink to the dermis using a tattoo device (eg, a tattoo gun). The carrier for the dye, eg water, is absorbed and the insoluble dye particles remain in the initially deposited dermis. Inactivation and aggregation result in the deposition of tattoo ink particles, preventing the immune system from removing the tissue from the interstitial space, thus leading to its permanent effect.

[0004] Over the years, personal style, interests, and cutis laxa may evolve. Tattoos can be removed using laser-based methods, but such methods are relatively expensive and cannot completely remove tattoos. In addition, surgical removal, desquamation, and salabrasion are invasive removal procedures that can lead to scarring. To avoid these shortcomings, some people change to paints that can be painted on the skin (eg henna). However, these paints are easily washed off and do not give the recipient the true sensation of having a somewhat permanent tattoo. There is a need for semi-permanent tattoos that can retain their vividness for about 2 to about 12 months.

[Overview]
[0005] Various techniques and reagents useful in a particular embodiment of the device can be readily used by one of ordinary skill in the art to benefit from the present disclosure. Additional features such as adhesives, covers such as bandages, pre-loaded syringes for intradermal injection, etc. can be easily incorporated. For example, the device can be injected into the subject, or the device can be administered to or inserted into the skin of the subject.

[0006] One aspect of the present disclosure relates to a composition comprising particles and a carrier solution. In one embodiment, the particles include a shell and a core. In one embodiment, the shell comprises a polymer that is bioabsorbable and biodegradable. Exemplary polymers include polycaprolecton (PCL), poly D-lactic acid (PDLA), polyL lactic acid (PLLA), poly (lactic acid-co-glycolic acid), (PLGA), polyethylene glycol (PEG), polyethylene. Includes glycol-diacrylate (PEGDA), polyorthoesters, aliphatic polyanhydrides, and / or aromatic polyanhydrides, or block polymers thereof.

[0007] In one embodiment, the core comprises a coloring agent having a molecular weight of from about 5 to about 10 × 10 ⁶ daltons.

[0008] In one embodiment, the carrier solution is a liquid, solid, semi-solid, gel, paste, or wax.

[0009] In one embodiment, the particles are about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 15 μm, about 10 μm, about 9 μm, about 8 μm, It has a diameter of about 7 μm, 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, about 1 μm, or about 0.5 μm or less. In one embodiment, the particles are sized to induce agglutination when incorporated into the dermis of an animal or human.

[0010] In one embodiment, the polymer is present in the shell at a concentration effective to induce agglutination when incorporated into the dermis of an animal or human. Although not bound by any particular theory, hydrophobic interactions result in particle agglutination in a physiological environment. In one embodiment, electrostatic interactions, cross-linking through surface groups, and / or polyelectrolyte interactions cause particle aggregation in the dermis of animals or humans. In one embodiment, the polymer is present in the particles in an amount sufficient to prevent or inhibit the phagocytosis of the colorant.

[0011] In one embodiment, the shell is about 0.2 μm to 10 μm, about 0.3 μm to 9 μm, about 0.4 μm to 8 μm, about 0.5 μm to 7 μm, about 0.6 μm to 6 μm, about 0.7 μm. It has a thickness of ~ 5 μm, about 0.8 μm to 4 μm, about 0.9 μm to 3 μm, and about 1 μm to 2 μm (including both ends).

[0012] In one embodiment, the polymer has a weight average molecular weight of 50 Da to 100 kDa (including both ends). In one embodiment, the polymer is crystalline, semi-crystalline, or amorphous. In one embodiment, the polymer is cationic, anionic, or zwitterionic at physiological pH. In one embodiment, the polymer undergoes surface or bulk erosion in aqueous solution. In one embodiment, the polymer, weight average molecular weight, and shell thickness are configured such that at least one of the bioabsorption profile and the biodegradation profile exhibits a delay stage of about 2 months to about 12 months. After the delay step, the colorant is rapidly released into the dermis, absorbed and / or degraded.

[0013] In one embodiment, the shell further comprises a temperature responsive polymer. In one embodiment, the temperature responsive polymer induces particle agglutination inducers when the composition is incorporated into the dermis of an animal or human. In a preferred embodiment, the particles aggregate at a temperature above about 98 ° F (body temperature) and the particles are non-aggregated at a temperature below 98 ° F. In some embodiments, the non-aggregating form of the particles facilitates administration and dispersion of the particles in the subject. In some embodiments, administration of the composition is achieved by intradermal injection. In one embodiment, the temperature responsive polymer is Pluronic® F-127. Pluronic® F-127 forms a gel above 10 ° C. at a concentration of 18-50%. It reliquefies when cooled below 10 ° C. In some embodiments, the heat responsive polymer is poly (N-isopropylacrylamide) (PNIPAM), which is about 0.1% to about 50%, about 0.2% to about 50%, in the shell. About 0.3% to about 50%, about 0.4% to about 50%, about 0.5% to about 50%, about 1% to about 50%, about 2% to about 50%, about 0.1 % ~ About 50%, about 3% ~ about 50%, about 4% ~ about 50%, about 5% ~ about 50%, about 10% ~ about 50%, about 15% ~ about 50%, about 20% ~ About 50%, about 25% to about 50%, about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 45% to about 50%, about 0.1% to About 49%, about 0.1% to about 48%, about 0.1% to about 47%, about 0.1% to about 46%, about 0.1% to about 45%, about 0.1% to About 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to About 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to It can be present in the range of about 2%, or about 0.1% to about 1% w / w (PNIPAM / particle weight).

[0014] In one embodiment, the colorant is a dye or dye. In one embodiment, the colorant is fluorescent or phosphorescent. In one embodiment, the colorant is present in the core in an amount of 1 ng to 1 μg (including both ends). In some embodiments, the composition comprises a colorant selected from one or a combination of the following non-limiting examples: melanin, [phthalocyaninato (2-)] copper, FD & C Red 40. (Food Red 17, Arla Red), FD & C Yellow 5, Ponceau, Reactive Black 5, Acid Blue 113, Brilliant black BN Granular (Food Black 1), D & C Yellow 10 , FD & C Blue 1 (Food Blue 2), FD & C Blue 2, Acid Black 1, Acid Black 24, Acid Black 172, Acid Black 194, Acid Black 210, Spirulina Extract Powder, Gardenia Yellow (Gardenia Yellow) 98%, Gardenia Yellow 40%, Gardenia Black, Gardenia Blue, Gardenia Red, Cochinil / Carmine, Anato, Beta Caroten, D & C Orange 4, D & C Red 33, D & C Red 22, Ext D & C Violet 2, D & C Yellow 8 , FD & C Green 3, FD & C Red 4, FD & C Yellow 6, FD & C Red 3, Ponceau 4R, Acid Red 52, Carmine, Amanas, Brown HT, Black PN, Green S, Patent Blue V, Tartrazine, Sunset Yellow, Kinolon Yellow, Erytrosin, Brilliant Blue, Indigo Carmine, D & C Green 5, D & C Red 17, D & C Red 21, D & C Red 27, D & C Yellow 11, D & C Violet 2, D & C Green 6, D & C Red 30, D & C Red 31 , D & C Red 28, D & C Red 7, D & C Red 6, D & C Red 34, D & C Yellow 10, Carmine Shin Lake, Ponso 4R Lake, Fanchon Yellow, Truisin Red, Acid Red 52 Lake, Arla Red Lake, Tartrazine Lake, Sunset Yellow Lake, Brilliant Blue Lake, Erythrosin Lake, Kinolin Lake, Indigo Carmine Lake, Lake Patent Blue V, Lake Black PN, Risole Rubin B, Iron Oxide Red, Iron Oxide Yellow , Iron oxide black, iron blue, titanium dioxide, D & C Red 36, Carbon Black, Ultra Marine Blue, Ultra Marine Violet, Ultra Marine Red / Pink, Chromium Oxide Green, Mica, Chromium Hydroxide Green, Tarku, Manganese Violet, Iron Oxide Burgundy, Iron Oxide Siena, Iron Oxide Tan, Oxidation Amber, Iron Oxide Brown-G, Iron Oxide Brown S, Sodium Copper Chlorophyllin, Caramel, Riboflavin, Cantaxanthin, Paprika, D & C Green 8, Ext D & C Yellow 7, NOIR Brilliant BN, Iron Ferocyanate (III) Ammonium, D & C Yellow 10 Lakes, FD & C Yellow 5 Lakes, FD & C Yellow 6 Lakes, D & C Red 21 Lakes, D & C Red 33 Lakes, FD & C Red 40 Lakes, D & C Red 27 Lakes, D & C Red 28 Lakes, FD & C Blue 1 Lakes, D & C Red 30 Lakes, D & C Red 36 rakes, D & C red 6 rakes, D & C red 7 rakes, D & C black 2. The colorant combination is intended by the present disclosure at a cosmetically effective concentration such that the release into the dermis or the degradation at the delayed stage is from about 2 months to about 12 months. Emission and decomposition of the contents of each particle layer can result in partial or complete color change in the tattooed design.

[0015] In one embodiment, the core consists of a colorant, which is an aggregate. In one embodiment, the particles have a diameter of about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, about 1 μm, or about 0.5 μm or less. In one embodiment, the colorant is dissolved or suspended throughout the particles and does not need to have a core-shell structure.

[0016] In one embodiment, the core further comprises a core polymer. In one embodiment, the polymer and core polymer are the same or different. In one embodiment, at least one of the polymer and the core polymer is a block copolymer. In one embodiment, the block copolymer comprises a diblock copolymer or a triblock copolymer. In one embodiment, the core polymer is about 7% -10%, about 10% -15%, about 15% -20%, about 20% -25%, about 25% -30%, about 30% -30%. , About 35% -40%, about 40% -45%, about 45% -50%, about 50% -55%, about 55% -60%, about 60% -65%, about 65% -70%, It is present in the particles at concentrations of about 70% to 75%, about 75% to 80%, about 80% to 85%, about 85% to 90%, or about 90% to 92% w / w.

[0017] In one embodiment, the colorant is either adsorbed on the core polymer, physically captured by the core polymer, or covalently attached to the core polymer. Although not desired to be constrained, we assume that as the core polymer decomposes, the colorant is released into the dermis along with the decomposed polymer components, both of which are removed by the body. In one embodiment, the colorant comprises a metal that forms a coordination bond with the core polymer. In one embodiment, the colorant is about 0.01% -10% w / w, 0.02% -9%, 0.03% -8%, 0.04% based on the total polymer weight of the particles. ~ 7%, 0.05% ~ 6%, 0.06% ~ 5%, 0.07% ~ 4%, 0.08% ~ 3%, 0.09% ~ 2%, 0.1% ~ 1 % (Including both ends) concentration.

[0018] In one embodiment, the core comprises hydrogel. In one embodiment, the colorant is adsorbed to the core polymer covalently attached to the hydrogel, physically captured by the core polymer, inserted into the core polymer, or non-covalently attached to the core polymer. , Or is covalently attached to the core polymer. In one embodiment, the hydrogels are alginate, chitosan hydrochloride, methacrylate-modified hyaluronic acid (HA-MA), thiolated hyaluronic acid (HA-SH), poly (N-isopropylacrylamide) (PNIPAM), and polyethylene glycol (PEG). Includes at least one of. In one embodiment, the hydrogel comprises a salt of such a hydrogel. In some embodiments, the colorant comprises a metal that forms a coordination bond with the hydrogel.

[0019] In one embodiment, the core further comprises at least one of the following: alginate, pectin, chitosan, hyaluronic acid, κ-carrageenan, agarose, agar, cellulose derivatives, carboxymethyl cellulose (CMC), protein based. Hydrophilic polymers, collagen hydrolysates, gelatin, synthetic hydrophilic polymers, polyacrylamide, polyacrylic acid, polyvinyl alcohol, polyethylene glycol (PEG) and modified PEG. In one embodiment, the shell or core is poly [bis (p-carboxyphenoxy) methane] (poly (CPM)), poly [1,3-bis (p-carboxyphenoxy) propane] poly (CPP), poly [ 1,6-bis (p-carboxyphenoxy) hexane] (poly (CPH)), poly (anhydrous sebacic acid) (poly (SA)), poly [1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxy Phosphate], and poly [1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate] -co-1,4-bis (hydroxyethyl) terephthalate-co-terephthalate (P (BHET-EOP / BHET), It further comprises at least one polyanhydride selected from the group consisting of 80/20). In one embodiment, the shell or core further comprises at least one polyorthoester (POE) selected from the group consisting of POE I, POE II, POE III, and POE IV. POE I, POE II, POE III, and POE IV are first, second, third, and fourth generation polyorthoesters, respectively. In one embodiment, the polyorthoester comprises a heterocycle.

である。一実施形態では、粒子は、担体溶液中に、約５〜約８、約８〜約１１、約１１〜約１４、約１４〜約１７、約１７〜約２０、約２０〜約２３、約２３〜約２５、約２５〜約２８、約２８〜約３１、約３１〜約３４、約３４〜約３７、約３７〜約４０、約３７〜約４０、約４０〜約４３、約４３〜約４５、約４５〜約４８、約４８〜約５０、約５０〜約５３、約５３〜約５５、約５５〜約５８、又は約５８〜約６０％ｗ／ｖの濃度で存在する。一実施形態では、組成物は、粒子中の浸透圧を少なくとも約２ヶ月〜約６０ヶ月間維持するのに十分な濃度である。 [0020] In one embodiment, the particles are about 5 to about 20, about 20 to about 50, about 50 to about 80, about 80 to about 110, about 110 to about 140, about 140 to about 170, about 170 to. At concentrations of about 200, about 200 to about 230, about 230 to about 250, about 250 to about 280, about 280 to about 310, about 310 to about 340, about 340 to about 370, about or about 370 to about 400 mg / ml. Present in carrier solution. The concentration of the particles can also be expressed as% w / v, where

Is. In one embodiment, the particles are contained in the carrier solution at about 5 to about 8, about 8 to about 11, about 11 to about 14, about 14 to about 17, about 17 to about 20, about 20 to about 23, about. 23 to about 25, about 25 to about 28, about 28 to about 31, about 31 to about 34, about 34 to about 37, about 37 to about 40, about 37 to about 40, about 40 to about 43, about 43 to It is present at concentrations of about 45, about 45 to about 48, about 48 to about 50, about 50 to about 53, about 53 to about 55, about 55 to about 58, or about 58 to about 60% w / v. In one embodiment, the composition is at a concentration sufficient to maintain the osmotic pressure in the particles for at least about 2 months to about 60 months.

[0021] In one embodiment, the composition further comprises a moisturizer, a biocide, a buffer, a surfactant, and / or a copolymer.

[0022] In one aspect of the present disclosure, the method of tattooing a subject comprises administering to the subject a composition as disclosed in this application. In one embodiment, the dosing step comprises intradermal administration of a cosmetically effective amount of the composition as disclosed herein.

[0023] In one embodiment, the method of inhibiting the absorption of a colorant in the skin of a subject comprises encapsulating the colorant in any of the particles disclosed herein.

[0024] Another aspect of the present disclosure relates to a method of treating a pigment disorder in a subject in need of treatment of the pigment disorder, wherein the method comprises a therapeutically effective dose of a portion of the skin of the subject having dysfunctional pigment secretion. The step of contacting with the particles according to any one of claims 1 to 44 is included.

[0025] The particles of the present disclosure are particularly useful for administration of active medical agents. The composition includes pediatrics, elderly patients, and / or persons suffering from mental illness (those who are difficult to test and uncooperative), as well as the military, and people without health insurance (eg, low-income and /). Or it can be especially useful for homeless people).

[0026] In one set of embodiments, the method comprises the act of altering the coloration of a colorant embedded in a subject by applying electrical, magnetic, and / or mechanical forces to the subject. Yet another set of methods comprises the act of determining a sample in a subject by determining particles having at least two distinct regions in the subject, each region on the surface of the particle. exist.

[0027] A method according to yet another set of embodiments is to provide a first particle having at least two separate regions, each region being present on the surface of the first particle and a first. The particles of the particle contain the first colorant and provide; the second particle (in some embodiments, it may have at least two separate regions, each region of the second particle. To provide (which is present on the surface), the second particle contains and provides a second colorant; the first colorant and the second colorant can react. As such, it involves the act of immobilizing the first and second particles with respect to each other.

[0028] Yet another embodiment generally relates to a device for delivering multiple particles to the dermis or epidermis of interest. According to a set of embodiments, the device is detachably connected to the substrate and optionally carries a colorant, a plurality of epidermal and / or dermal insert objects (as used herein). Includes "skin insertion object"). In some cases, the substrate is constructed and arranged to apply multiple epidermal and / or dermis insert objects to the skin of interest and facilitate introduction of such objects into the epidermis and / or dermis, where the object is the dermis. And / or when delivered to the epidermis, when the substrate is removed from the skin, at least a portion of the object is secured to the plurality of objects with a degree of adhesion such that at least part of the object remains in the dermis and / or the epidermis. ..

[0029] Yet another aspect generally relates to a kit for delivering a colorant to the dermis and / or the epidermis. According to a set of embodiments, the kit comprises multiple skin inserts, at least some of which carry a fine particle composition containing a colorant, where the multiple skin inserts are applied to the skin. , At least some of the particulate composition is delivered to the dermis and / or the epidermis and is constructed and placed to remain in the dermis and / or the epidermis for a cosmetically acceptable time.

[0030] Although not bound by any particular theory, we believe that following the injection of ink particles onto an area of the skin, such ink particles form large aggregates. It is assumed that it exists in the interstitial space between the dermal cells. In addition, tattoo ink particles cause a foreign body inflammatory reaction composed of epithelioid cells, lymphocytes, and giant cells that swallow foreign tattoo ink particles and ink particle aggregates to try to internalize them. Macrophages and dendritic cells become hypertrophied and develop into epithelioid cells and multinucleated giant cells. This type of reaction, the size of the ink particle agglomerates, and the collagen network surrounding the agglomerates are primarily responsible for the long-term retention of tattoo ink in the dermis. Thus, after administration of the tattoo ink to the dermis, the tendency of particle agglutination is important for maintaining tattoo stability during the delayed stages in which the shell is expected to be bioabsorbed and / or biodegraded. Smaller particles have a higher agglomeration tendency due to their larger surface area. Therefore, an appropriate particle size range is needed to ensure agglomeration and achieve good tattoo vividness over a long period of time. In some embodiments, the particle size is about 100 microns or less in diameter.

[0031] A schematic diagram of particles is shown.

[Detailed description of the embodiment]
Prior to describing the compositions and methods of the invention, it should be understood that the present disclosure is not limited to the particular molecules, compositions, methodologies or protocols described and these may vary. .. Also, the terms used herein are for the purposes of describing a particular version or embodiment only and are intended to limit the scope of the present disclosure, which is limited solely by the appended claims. It should be understood that it is not a thing. It is understood that these embodiments are not limited to the particular methods, protocols, compositions, polymers, particles, and reagents described, and these can vary. It is also understood that the terminology used herein is intended only to describe a particular embodiment and is not intended to limit the scope of the present embodiment or claims.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any method and material similar to or equivalent to that described herein can be used in the embodiments or tests of the embodiments of the present disclosure, but preferred methods, devices, and materials are described herein. All publications listed herein are incorporated herein by reference. Nothing herein is to be construed as acknowledging that this disclosure does not precede such disclosure by means of prior disclosure.

[0034] The indefinite articles "a" and "an" used herein and in the claims should be understood to mean "at least one" unless expressly opposed. As used herein and in the claims, the phrase "and / or" is such a combined element, i.e., in some cases, present in combination and in other cases, separated. It should be understood to mean "either or both" of the elements that exist in the world. In addition to the elements specified in detail by the "and / or" section, there may be other elements, whether related to or not related to the elements specified in detail, unless explicitly opposed. You may. Thus, as a non-limiting example, when the reference to "A and / or B" is used in conjunction with an open-ended term such as "contains", in one embodiment A without B (case). (Including elements other than B); in another embodiment B without A (possibly including elements other than A); in yet another embodiment both A and B (possibly other elements) ); Etc. can be pointed out.

[0035] As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is inclusive, i.e., not only contains at least one of the numbers or list of elements, but also includes two or more. , It shall also be construed to include additional items that are not optionally listed. Only words that are clearly opposed, such as "only one of" or "exactly one of", or, when used in the claims, "consisting of", are of the element. Refers to containing exactly one element of a number or list. Generally, the term "or" as used herein is construed as indicating only an exclusive option (ie, "one or the other, but not both") when preceded by the term exclusivity. And when used in the claims, "any", "one of", "only one of", or "exactly one of", "from the essence" "Become a target" shall have its usual meaning as used in the field of patent law.

[0036] As used herein, the term "about" refers to a measurable value such as quantity, time length, etc., from a particular value, as appropriate to carry out the disclosed method. ± 20%, ± 10%, ± 5%, ± 1%, ± 0.9%, ± 0.8%, ± 0.7%, ± 0.6%, ± 0.5%, ± 0.4 It means to include a variation of%, ± 0.3%, ± 0.2% or ± 0.1%.

[0037] As used herein, the phrase "integer from X to Y" means any integer, including endpoints. That is, when the range is disclosed, each integer in the range including the end point is disclosed. For example, the phrase "integer of X to Y" discloses 1, 2, 3, 4, or 5 as well as the range 1-5.

[0038] As used herein, the terms "preparing" (and any form such as "comprise", "comprises", and "comprised"), "having". (And any form such as "have" and "has"), "include" (and any form such as "includes" and "include"), or "Contains" (and any form such as "contains" and "contain") is inclusive or open-ended and does not exclude additional, unreferenced element or method steps. ..

[0039] FIG. 1 shows a graphical representation of bioabsorption and / or biodegradation of an embodiment of the particles of the present disclosure over 100 days. FIG. 1A shows particles having a core containing a colorant, an inner shell containing a bioabsorbable and / or biodegradable polymer or hydrogel, and an outer shell containing a bioabsorbable and / or biodegradable polymer. FIG. 1B is a diagram of an embodiment of a particle on day 0, which is the day the particle is injected into the skin of an animal or human. By day 70, the thickness of the outer shell had decreased due to bioabsorption and / or biodegradation, as shown in FIG. 1C. For these 70 days, the colorant remains substantially encapsulated by the inner and outer shells, and the tattoo color is a delayed stage that appears bright under animal or human skin. As shown in FIG. 1D, on about 85 days, both the inner and outer shells were sufficiently degraded to allow release of the colorant. FIG. 1E shows the dispersion, absorption and / or decomposition of the colorant, the tattoo gradually fading. By day 100, colorants and tattoos are no longer clear (Fig. 1F).

[0040] In one embodiment, the composition is provided, wherein the composition is (i) a particle, wherein the particle is (a) a shell comprising a bioabsorbable and biodegradable polymer and (b) a shell. A core comprising either a similar or different bioabsorbable and biodegradable polymer or a hydrogel matrix and a colorant having a molecular weight of ^{about 5 to about 10 × 10 6 (including both ends) Dalton;} The agent is inserted into a polymer or hydrogel matrix and is non-covalently or covalently bonded, and the bioabsorbable and biodegradable polymers are homopolymers, copolymers, polycaprolecton (PCL), polyL-lactic acid (PLLA). , Poly (lactic acid-co-glycolic acid) (PLGA), polyethylene glycol (PEG), polyethylene glycol-diacrylate (PEGDA), polyorthoesters, aliphatic polyanhydrides, or aromatic polyanhydrous. Or the particles comprising a block polymer having two, three or more blocks selected from the combination (eg, diblock or triblock polymers) and (ii) carrier solution.

[0041] Another embodiment provides a composition, wherein the composition is: (i) particles, the particles are (a) a shell containing a bioabsorbable and biodegradable polymer, and (b) about. Includes a core containing a colorant having a molecular weight of 5 to about 10 × 10 ⁶ (including both ends) Dalton, the colorant being encapsulated by the shell polymer, and the shell bioabsorbable and biodegradable polymer being polyca. Prolecton (PCL), poly L-lactic acid (PLLA), poly (lactic acid-co-glycolic acid) (PLGA), polyethylene glycol (PEG), polyethylene glycol-diacrylate (PEGDA), polyorthoester, aliphatic polyanhydrous Particles comprising a first block or diblock polymer selected from one or a combination of a product, poly (sebasic acid anhydride) (poly (SA)), or aromatic polyanhydrous, and (ii) carrier. Includes solution.

[0042] As used herein, a "particle" is a minute portion of a substance. The particles may be microparticles and / or nanoparticles. "Microparticles" are particles with an average diameter on the order of micrometers (ie, about 1 micrometer to about 1 mm), while "nanoparticles" are particles on the order of nanometers (ie, about 1 nm to about 1). Particles with an average diameter of (micrometers). In some cases, multiple particles can be used, and in some cases, some or substantially all of the particles may be the same. For example, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about particles. About 90%, at least about 95%, or at least about 99% may have the same shape and / or may have the same or dissimilar composition.

[0043] The particles can be formed of any suitable material, depending on the application. For example, the particles are glass and / or polymers such as polyethylene, polystyrene, silicone, polyfluoroethylene, polyacrylic acid, polyamide (eg nylon), polycarbonate, polysulfone, polyurethane, polybutadiene, polybutylene, polyethersulfone, poly. It may include etherimide, polyphenylene oxide, polymethylpentene, polyvinylidene chloride, polyvinylidene chloride, polyphthalamide, polyphenylene sulfide, polyester, polyetheretherketone, polyimide, polymethylmethacylate and / or polypropylene. In some cases, the particles can include ceramics such as tricalcium phosphate, hydroxyapatite, fluoroapatite, aluminum oxide, or zirconium oxide. In some cases (eg, in certain biological applications), the particles are biocompatible and / or biodegradable polymers such as polylactic acid and / or polyglycolic acid, polyanhydrides, polycaprolactones, polyorthoesters. It can be formed from esters, polyethylene oxides, polybutylene terephthalates, starches, celluloses, chitosans, and / or combinations thereof. In a set of embodiments, the particles can include hydrogels such as agarose, collagen, or fibrin.

[0044] The particles may optionally include a magnetically sensitive material, such as a material exhibiting paramagnetism or ferromagnetism. For example, the particles can include iron, iron oxide, magnetite, hematite, or any other compound containing iron. In another embodiment, the particles are a conductive material (eg, a metal such as titanium, copper, platinum, silver, gold, tantalum, palladium, rhodium) or a semiconductor material (eg, silicone, germanium, CdSe, CdS, etc.). Can be included. Other particles include ZnS, ZnO, TiO ₂ , AgI, AgBr, HgI ₂ , PbS, PbSe, ZnTe, CdTe, In ₂ S ₃ , In ₂ Se ₃ , Cd ₃ P ₂ , Cd ₃ As ₂ , InAs, or. Includes GaAs.

[0045] Particles are cells, biochemical species such as nucleic acids (eg, RNA, DNA, PNA, etc.), proteins, peptides, enzymes, nanoparticles, quantum dots, fragrances, indicators, dyes, fluorescent species, chemicals. , Small molecules (eg, having a molecular weight of less than about 1 kDa) and the like. In some embodiments, in addition to containing one or more reactants and / or one or more signal transduction agents, the particles also contain one or more colorants.

[0046] In some embodiments, the particles contain one or more colorants. As used herein, a "colorant" is a dye, dye, or any compound that emits light with a wavelength that is visible spectrum when exposed to visible or ultraviolet light. In some embodiments, the colorant is a dye. As used herein, "dye" refers to a colored molecule that is liquid or soluble in a liquid vehicle. In some embodiments, the colorant is a dye. As used herein, "dye" refers to a colored molecule that is insoluble in a liquid vehicle. In some embodiments, the colorant is one or more fluorescent dyes. In some embodiments, the colorant is a combination of two or three of the aforementioned species.

[0047] In one embodiment of the invention, a tattoo ink that remains in the dermis for a predetermined period of time (eg, 2, 3, 6, 9, months, or 1, 2, 5, 10 years, etc.) and then spontaneously disappears. Is provided. These "semi-permanent" or "temporary" tattoo inks allow the dye or colorant to be slowly bioabsorbed, bio-eroded, mixed and / or biodegraded over a predetermined period of time. At a cosmetically effective concentration or amount, the appropriate pigment or colorant (a pigment that is easily eliminated if it is present in the dermis) is captured, wrapped, complexed, incorporated, or incorporated into the vehicle. Manufactured by encapsulation. In some embodiments, the dye or colorant slowly biodegrades at a constant rate over a period of about 5 years, 4 years, 3 years, 2 years, 1 year or 6 months, or a specific percentage of the vehicle. Once absorbed, the dye can be released over a short period of time. For example, all dyes can be released during the 4th to 5th years, or any 1 month period of about 2 to about 60 months.

[0048] In some cases, the "tattoo" or particles contained within the skin can be altered by the administration of electrical, magnetic, and / or mechanical forces to the subject. For example, by applying such a force, the particles can be clustered, which can result in a color change, as described above. Accordingly, one embodiment of the present disclosure is an external stimulus such as electrical, magnetic, and / or mechanical force, and / or a chemical that is applied to the skin (eg, a chemical that is a binding partner of a species on a particle). ) The area within the subject's skin that can be modified by application. In some embodiments, areas of the skin can only be modified by adsorption and / or decomposition of particles without electrical, magnetic, or mechanical forces.

[0049] The tattoo (or other mark) present on the skin can have any function, for example as a decorative art or as an identification system. For example, a tattoo can be verified by applying a stimulus (eg, electric field, magnetic field, mechanical force, chemical substance, etc.) to the subject and confirming the tattoo by identifying changes in the mark such as color changes. .. Mark changes may be permanent or temporary. As a specific example, the stimulus may be applied to anisotropic particles containing a first region showing a first color and a second region showing a second color. In the absence of stimuli, the particles show a mixture of first and second colors, but under the application of stimuli, only one color can be shown as the particles align. The identification of this color change can be used, for example, artistically or as an identification mark. As mentioned above, in some cases such marks may be permanent or temporary. As another example, particles can be invisible (eg, non-aggregated) in the absence of a stimulus, but can be visible (eg, aggregated) when a stimulus is applied. In some cases, the particles change their appearance while the stimulus is applied, but return to their original appearance when the stimulus is removed; however, in other cases, the particles are after the stimulus is removed. The altered appearance can be retained over time, and in some cases the particles retain the altered appearance forever.

[0050] As used herein, the "dermis" is a thick layer of living tissue beneath the epidermis that forms one layer of skin. The dermis can include capillaries, nerve endings, sweat glands, hair follicles, connective tissue, lymph vessels, and other structures. The epidermis is the outermost layer of skin and contains cells that make and store melanin pigments.

[0051] As used herein, "biodegradable" or "bioerodible" means that it can be degraded by a natural process. In some embodiments, the natural process occurs within the subject's body. Similarly, as used herein, "bioabsorbable" means that it can be absorbed by living tissue.

Any conventional colorant suitable for tattoos, as well as any biologically acceptable color, can be used for the color elements of the tattoo inks of the present invention. The Food and Drug Administration states that the pigments used in tattoos are the Federal Food, Drug and Cosmetic Act. [Cf. 21 USC Sections 32l (t) and 379 (e)]). It is considered to be a "color additive" subject to the regulation of FDA color additives based on. In addition, substantially any body-acceptable dye or colorant can be used as a suitable tattoo ink when mixed with the vehicle to form the dye / vehicle complex according to the invention. Non-limiting examples of colorants used in the present invention include melanin, [phthalocyanine (2-)] copper, FD & C red 40 (hood red 17), FD & C yellow 5, niglocin, reactive black 5, Acid Blue 113, Brilliant Black BN Granules (Food Black 1), D & C Yellow 10, FD & C Blue 1 (Food Blue 2), FD & C Blue 2, Acid Black 1, Acid Black 24, Acid Black 172, Acid Black 194, Acid Black 210 , Spirulina Extract Powder, Gardenia Yellow 98%, Gardenia Yellow 40%, Gardenia Black, Gardenia Blue, Gardenia Red, Cochinil / Carmine, Anato, Beta Carotene, D & C Orange 4, D & C Red 33, D & C Red 22, Ext D & C Violet 2 , D & C Yellow 8, FD & C Green 3, FD & C Red 4, FD & C Yellow 6, FD & C Red 3, Ponso 4R, Acid Red 52, Carmoicin, Amanas, Brown HT, Black PN, Green S, Patent Blue V, Tartrazin, Sunset Yellow , Iron Oxide Yellow, Erytrosin, Alla Red, Brilliant Blue, Indigo Carmine, D & C Green 5, D & C Red 17, D & C Red 21, D & C Red 27, D & C Yellow 11, D & C Violet 2, D & C Green 6, D & C Red 30, D & C Red 31, D & C Red 28, D & C Red 7, D & C Red 6, D & C Red 34, D & C Yellow 10, Carmoicin Lake, Ponso 4R Lake, Fancy Yellow, Truisin Red, Acid Red 52 Lake, Alla Red Lake, Tartradine Lake, Sunset Yellow Lake, Brilliant Blue Lake, Elytrosin Lake, Kinolin Lake, Indigo Carmine Lake, Lake Patent Blue V, Lake Black PN, Risole Rubin B, Iron Oxide Red, Iron Oxide Yellow, Iron Oxide Black, Iron Blue , Titanium dioxide, D & C Red 36, Carbon Black, Ultra Marine Blue, Ultra Marine Violet, Ultra Marine Red / Pink, Iron Oxide Green, Mica, Chromium Hydroxide Green, Tarku, Manganese Violet, Iron Oxide Burgundy, Iron Oxide Siena, Oxidation Iron tan, iron oxide amber, iron oxide brown G, iron oxide brown S, sodium copper chlorophyllin, caramel, riboflavin, canta Xanthin, paprika, D & C green 8, Ext D & C yellow 7, NOIR brilliant BN, ferrous ferrocyanide ammonium, D & C yellow 10 rake, FD & C yellow 5 rake, FD & C yellow 6 rake, D & C red 21 rake, D & C red 33 rake, FD & C Red 40 rakes, D & C Red 27 rakes, D & C Red 28 rakes, FD & C Blue 1 rakes, D & C Red 30 rakes, D & C Red 36 rakes, D & C Red 6 rakes, D & C Red 7 rakes, D & C Black 2 rakes.

[0053] An example of a particle that continuously releases a colorant over a predetermined period is one in which the colorant is incorporated or mixed into the entire substance of the vehicle to form colored particles. When these colorant / vehicle complexes are introduced into the dermis (in the form of tattoos), the tattoo colorant and vehicle are slowly bioabsorbed, releasing the colorant from the dissolved vehicle and removing the colorant from the dermis. The tattoo is no longer visible when all of the colorant / vehicle has been absorbed.

[0054] Bioabsorbable microcapsules or microflakes can be used as vehicles to release the colorant in a short period of time. In microcapsules, the colorant / vehicle complex contains a colorant core surrounded by a vehicle, until a particular threshold percent of vehicle is dissolved, eroded, or absorbed. , Maintain its integrity. At this point, the vehicle no longer protects the colorant from exclusion. The colorant is released into the dermis where it is eliminated in a relatively short time.

Alternatively, a microflake made from a colorant and a vehicle, wherein the colorant is mixed throughout the microflake, maintains a relatively consistent colorant surface area during the process of bioabsorption. .. Over a given period of time, the visible colorant surface melts similar to the melting of a frozen lake or pond.

[0056] The vehicle for the colorant comprises any biologically acceptable material that retains the colorant in the dermis for any time or under any desired conditions. In any of these cases, the vehicle carries a colorant, which can be administered into the dermis in any pattern or composition in a manner similar to traditional tattoos. The vehicle is sufficiently transparent or translucent so that the color of the colorant can be seen through.

[0057] Among other materials that can function as a tattoo colorant vehicle in the present invention, some have found that the FDA is acceptable for use as a food additive, including succinylated gelatin. , Arabinogalactan, glutaraldehyde, petroleum wax, and mixtures thereof. Additional materials for use as the tattoo colorant vehicle according to the invention include poloxanele, poly (co-hypophospholite) sodium salt, polyacrylamide, alginate / alginic acid, calcium caseinate, polypectinic acid. Calcium, phthalate acetate cellulose, cellulose acetate trimellitate, chitosan, edible and natural waxes, fatty acids, fatty alcohols, gellan gum, hydroxycellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylethylcellulose, hydropropylethylcellulose, hydroxypropylmethylcellulosephthalate, lipids , Mono-, di- and triglycerides, pectin, phospholipids, polyalkyl (C _16- C ₂₂ ) acrylate, polyethylene, polyethylene oxide, polyethylene imine reacted with 1,2-dichloroethane, polyoxyethylene (600) dioleate, poly. Oxyethylene (600) monolithinolate, polyoxyethylene (23) lauryl ether, polyethylene glycol, polyethylene glycol (400) dioleate, polyethylene glycol (400) mono- & dioleate, polyglycerol ester of fatty acids, polyisobutylene, coconut oil Polyglycerol phthalate ester of fatty acids, polymaleic acid and / or sodium salts thereof, polyoxyethylene glycol (400) mono- & dioleate, polyoxyethylene glycol (23) lauryl ether, polyoxyethylene (40) monostearate, polyoxy Ethylene-polyoxypropylene block polymer, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (2) sorbitan tristearate, polyoxypropylene glycol, polyvinyl acetate, Includes polysorbate 80, polyvinylpolypyrrolidone, polyvinylpyrrolidone, and poly (20 vinylpyridine-co-styrene).

[0058] As used herein, "modified PEG" is any polyethylene glycol derivative, eg, polyethylene glycol in which one or both of the terminal hydroxyl groups is pre-modified. Suitable PEG derivatives include alkoxy PEG in which the terminal hydroxyl group is converted to an alkoxy group.

[0059] Other materials for forming the tattoo colorant vehicle are biologically acceptable, wax, polyolefin, or paraffin (eg, yamamomo, whale wax, lacquer, Ross, etc.), triglyceride, phosphorus. Lipids, fatty acids and esters thereof (eg, lauric acid, palmitic acid, sorbitan monopalmitate, sorbitan monostearate, etc.), poly (vinyl palmitate), poly (hexadecyl acrylate), poly (butyl acrylate), poly (hexa). Decyl acrylate), poly (octadecyl acrylate), poly (dodecene), poly (isobutene), poly (trimethylglutarate), polyanhydrous, polyorthoester, polyester, polystyrene, polyurethane, polypropylene, polymethacrylate, polytetrafluoroethylene , Ceramics, or glass.

[0060] The amount of colorant used with the vehicle depends on the desired color and intensity of the colorant, as well as the color and texture of the skin to which the colorant should be administered. To form a tattoo ink, the tattoo colorant / vehicle complex is formed into a microstructure of the desired composition and shape, at a concentration sufficient to produce the desired coloration of the skin, with ethanol or water, or any. Suspended in a carrier such as another conventional tattoo ink liquid. Alternatively, the tattoo colorant / vehicle complex, like many traditional tattoo inks, is in the form of a suspension in a semi-liquid paste. The size of the tattoo colorant / vehicle complex is selected so that the ink is easily administered into the dermis with conventional tattoo ink devices.

[0061] To produce semi-permanent tattoos, colorants are captured, encapsulated, complexed and incorporated into vehicles composed of bioabsorbable, bioerodible or biodegradable materials. , Encapsulated, or otherwise associated. This material is designed to be bioabsorbed, eroded, or biodegraded over a predetermined period of time so that the tattoo ink, when administered to the dermis, is only bioabsorbed until the tattoo colorant vehicle is bioabsorbed. Produces a non-persistent tattoo. Upon partial or complete bioabsorption of the tattoo colorant vehicle, the colorant is released, allowing its elimination from the dermis.

[0062] There are numerous biodegradable polymers, and the length of time that a tattoo lasts visibly in the dermis is determined by controlling the type and composition of the vehicle's material. Among the bioabsorbable, bioerodible or biodegradable polymers that can be used are Higuchi et al., US Pat. Nos. 3,981,303, 3,986,510 and 3,995,635. Some of which are disclosed in the issue, including zinc alginate poly (lactic acid), poly (vinyl alcohol), polyanhydride and poly (glycolic acid). Alternatively, microporous polymers including those disclosed in Wong's US Pat. No. 4,853,224, such as polyesters and polyethers, and Kaufman's US Pat. Nos. 4,765,846 and 4,882. The one disclosed in No. 150 is appropriate.

[0063] Other polymers that slowly decompose in vivo are disclosed in Davis et al., US Pat. No. 5,384,333, which are solid at 20-37 ° C and have a temperature range of 38-52 ° C. It is a biodegradable polymer that is fluid and is, for example, a liquid. When preparing a semi-permanent tattoo, a colorant can be incorporated into the polymer matrix and the system heated to about 50 ° C., where it can be liquefied. The system is then injected into the dermis with the desired tattoo design, where it is cooled and resolidified.

[0064] For vehicles that melt, break, weaken, or decompose when heated, for example, melting temperatures of about 40 ° C to about 55 ° C are useful. Examples of such thermally unstable or meltable materials for the manufacture of vehicles include, but are not limited to, those listed in Table 1 or combinations thereof:

[0065] For this type of semi-permanent vehicle, any biodegradable polymer system having the following characteristics can be used, including homopolymers, copolymers, block copolymers, waxes and gels, and mixtures thereof. Preferred polymer systems are the general formula: [ABA] _x (where A represents a hydrophobic polymer block, B represents a hydrophilic polymer, and X represents from about 1 to about 90,000. It is a triblock copolymer (representing any positive integer). The monomers and polymers are preferably linked via ester groups. Preferred hydrophobic polymers and oligomers include polyglycolic acid, polyethylene terephthalate, polybutyllactone, polycaprolactone, D-polylactic acid, polytetrafluoroethylene, polyolefin, polyethylene oxide, polylactic acid, polyglutamic acid, poly-L-lysine, etc. And units selected from, but not limited to, poly-L-aspartic acid. Preferred hydrophilic polymers include polyethylene glycol, polypropylene glycol, and poly (vinyl alcohol).

[0066] In a preferred embodiment, the particle core is a colorant and polycaprolactone (PCL), poly D-lactic acid (PDLA), poly L-lactic acid (PLLA), poly (lactic acid-co-glycolic acid), (. Biodegradation containing at least one of PLGA), polyethylene glycol (PEG), polyethylene glycol-diacrylate (PEGDA), polyorthoesters, aliphatic polyanhydrides, and aromatic polyanhydrous, or block polymers thereof. Includes sex and / or biodegradable polymers. The colorant can be incorporated into the core polymer by including the colorant in the prepolymer mixture and subsequently polymerizing. In one aspect of the present disclosure, the polymerization process is an emulsion polymerization process. The colorant can also be incorporated into the core polymer by dissolving the polymer and the colorant in a solvent and then evaporating the solvent. In another aspect of the present disclosure, solvent evaporation is a single or double emulsion solvent evaporation process. The colorant can also be incorporated into the core polymer by melting the core polymer and dissolving and / or suspending the colorant directly in the neat polymer melt. It should be recognized that such methods can be used to incorporate colorants into polymers to form layerless particles and / or particle shells.

A hydrogel matrix or vehicle for preparing semi-permanent tattoo inks is formed by cross-linking a polysaccharide or mucopolysaccharide with a protein and loading a colorant into the hydrogel matrix. The protein comprises both a full-length protein and a polypeptide fragment, in which case it may be naturally, recombinantly produced, or chemically synthesized. Polysaccharides include both polysaccharides and mucopolysaccharides.

[0068] Hydrogels capable of incorporating colorants into tattoo inks are disclosed in Feijen US Pat. No. 5,041,292. The hydrogel comprises a protein, a polysaccharide, and a cross-linking agent, the cross-linking agent providing network binding in a weight ratio of polysaccharide to protein in the matrix in the range of about 10:90 to about 90:10. The colorant is mixed with the hydrogel matrix in an amount sufficient to color when administered to the dermis.

[0069] Examples of suitable polysaccharides include heparin, fractionated heparin, heparin, heparan sulfate, chondroitin sulfate, and dextran, which are described in US Pat. No. 4,060,081 to Yannas et al. Contains compounds. The use of heparin or heparin analogs is preferred as it appears to reduce immunogenicity. The protein component of the hydrogel can be either a full-length protein or a polypeptide fragment. The protein can be in natural form, recombinantly produced form, or chemically synthesized form. The protein composition can also be a mixture of full-length proteins and / or fragments. Typically, the protein is selected from the group consisting of albumin, casein, fibrinogen, gamma globulin, hemoglobin, ferritin and elastin. The protein component may also be a synthetic polypeptide such as poly (a-amino acid), polyaspartic acid or polyglutamic acid. Albumin is a preferred protein component of the matrix as it is an endogenous substance that is biodegradable in blood and tissues by proteolytic enzymes. In addition, albumin prevents the attachment of platelets and is non-toxic and non-hypergenic.

[0070] When forming a hydrogel containing a colorant, the polysaccharide or mucopolysaccharide and protein are dissolved in an aqueous medium, followed by the addition of an amide bond forming crosslinker. Preferred cross-linking agents for this process are carbodiimides, preferably water-soluble diimides such as N- (3-dimethylaminopropyl) -N-ethylcarbodiimide. In this method, the cross-linking agent is added to the aqueous solution of polysaccharide and protein at acidic pH and a temperature of about 0 ° C. to 50 ° C., preferably about 4 to about 37 ° C. and allowed to react for up to about 48 hours. The hydrogel so formed is then typically isolated by centrifugation and washed with a suitable solvent to remove unbound material.

Alternatively, the selected polysaccharide or mucopolysaccharide-protein mixture is treated with a cross-linking agent having at least two aldehyde groups to form Schiff base bonds between the components. These bonds are then reduced with a suitable reducing agent to give a stable carbon-nitrogen bond.

After the hydrogel is formed, the hydrogel is loaded with the colorant by immersing the hydrogel in a solution or dispersion of the colorant. The solvent is then evaporated. After equilibration, the loaded hydrogel is dried and stored in vacuum under ambient conditions.

[0073] Examples of preferred embodiments of polymers used in the preparation of hydrogel vehicles are alginate, alginate in combination with chitosan hydrochloride, methacrylate-modified hyaluronic acid (HA-MA), thiolated hyaluronic acid (HA-SH), poly. (N-Isopropylacrylamide) (PNIPAM), Polyethylene Glycol (PEG), Polycaprolectone (PCL), Poly L-Lactic Acid (PLLA), Poly (Lactic Acid-co-Glycolic Acid) (PLGA), PCL, PLLA, PLGA or Diblock or triblock polymers in any combination of PEG, polyethylene glycol-diacrylate (PEGDA), polyorthoesters, and / or aliphatic or aromatic polyanhydrides, or aliphatic or aromatic homopolyanhydrides such as poly. [Bis (p-carboxyphenoxy) methane] (poly (CPM), poly [1,3-bis (p-carboxyphenoxy) propane] (poly (CPP))), poly [1,6-bis (p-carboxyphenoxy) ) Hexane] (poly (CPH)), poly (sevacinic anhydride) (poly (SA)), poly [1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate], and / or poly [1, 4-] Bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate] -co-1,4-bis (hydroxyethyl) terephthalate-co-terephthalate (P (BHET-EOP / BHET), 80/20) Includes one or a combination.

[0074] Substantially any colorant can be loaded into the hydrogel vehicle if surface issues such as surface charge, size, shape, and hydrophilicity are taken into account. For example, incorporation and release of high molecular weight colorants will typically require hydrogels with a lower degree of cross-linking. The release of the charged colorant will be strongly influenced by the charge and charge density available in the hydrogel, as well as the ionic strength of the surrounding medium.

[0075] The rate of colorant release from the vehicle can also be affected by post-treatment of hydrogel preparation. For example, heparin concentration on the surface of a hydrogel can be increased by reaction of the prepared hydrogel with activated heparin (ie, heparin reacted with carbonyldiimidazole and saccharin) or heparin containing one aldehyde group per molecule. can. High concentrations of heparin on the surface of hydrogels will form an extra "barrier" for colorants that are positively charged at physiological pH values. Another way to achieve the same result is to treat the hydrogel with a positively charged polymer compound such as protamine sulfate, polylysine, or a polymer similar to these. Another way to change the hydrogel permeability is to treat the surface with a biodegradable block copolymer containing both hydrophilic and hydrophobic blocks. Hydrophilic blocks can be positively charged polymers such as polylysine, while hydrophilic blocks are biodegradable polys (L-alanine), poly (L-leucine), or similar polymers. It can be α-amino acid).

Another delayed release system used as a vehicle for colorants to form semi-permanent tattoos is colorants and enzymes encapsulated within microcapsules, which microcapsules are enzymes. It has a core formed from a polymer that is specifically degraded by and a speed control skin. When the core decomposes, the shell's integrity is lost, causing a sudden release of colorant from the capsule. In this type of system, the microcapsules consist of a core composed of a polymer, around which an ionically bonded skin or shell is present. The integrity of the skin or shell depends on the structure of the core. The enzyme is encapsulated with the bioactive substance to be released during the manufacture of the core of the microcapsules. The enzyme is selected to break down the core to the point where the core can no longer maintain the integrity of the skin, so that the capsule breaks down. An example of such a system consists of an ionicly crosslinked polysaccharide, calcium alginate ionicly coated with a polycationic skin of poly-L-lysine. The enzyme used to degrade calcium alginate coated with poly-L-lysine microcapsules is arginase from the bacterium Beneckea pelagio or Pseudomonas putida. There are enzymes that break down most naturally occurring polymers. For example, capsule cores can be formed from chitin for degradation by chitinase. Other natural or synthetic polymers can also be used and can be degraded with the appropriate enzyme (usually hydrogenase).

A particularly preferred bioabsorbable polymer vehicle is a triblock copolymer of polycaprolactone-polyethylene glycol-polycaprolactone. This polymer contains ester bonds that hydrolyze in a hydrophilic environment. In some embodiments, the biodegradable polymer matrix should contain from about 30% to about 99% particles.

[0078] In some embodiments, the core is alginate, chitosan hydrochloride, methacrylate-modified hyaluronic acid (HA-MA), tholated hyaluronic acid (HA-SH), poly (N-isopropylacrylamide) (PNIPAM). , And one or more of polyethylene glycol (PEG).

[0079] In some embodiments, the shell is polycaprolactone (PCL); poly L-lactic acid (PLLA); poly (lactic acid-co-glycolic acid) (PLGA); PCL, PLLA, PLGA or polyethylene glycol (PEG). ) In any combination of diblock or triblock copolymers; polyethylene glycol-diacrylate (PEGDA); polyorthoester (POE); poly (N-isopropylacrylamide) (PNIPAM); and aliphatic or aromatic polyanhydrides or Lipid-aromatic homopolyanhydrides such as poly (bis (p-carboxyphenoxy) methane) (poly (CPM)), poly (1,3-bis (p-carboxyphenoxy) propane) (poly (CPP)), Poly (1,6-bis (p-carboxyphenoxy) hexane) (poly (CPH)), poly (sevacinic anhydride) (poly (SA)), poly (1,4-bis (hydroxyethyl) terephthalate-alt- Ethyloxyphosphate) or poly (1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate) -co-1,4-bis (hydroxyethyl) terephthalate-co-terephthalate (P (BHET) -EOP / Includes one or more of BHET), 80/20). In some embodiments, the shell comprises any one or more of the above polymers and the total polymer weight / weight is about 5%, about 10%, about 15%, about 20%, about 25% of the particles. , About 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the shell comprises any one or more of the above polymers and the total polymer weight / weight is about 5% to about 15%, about 10% to about 20%, about 15% of the particles. ~ About 25%, about 20% ~ about 30%, about 25% ~ about 35%, about 30% ~ about 40%, about 35% ~ about 45%, about 40% ~ about 50%, about 45% ~ about 55%, about 50% to about 60%, about 55% to about 65%, about 60% to about 70%, about 65% to about 75%, about 70% to about 80%, about 75% to about 85% , About 80% to about 90%, about 85% to about 95%, or about 90% to about 99%.

[0080] In some embodiments, the shell comprises polycaprolactone (PCL) and the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% to about 15% of the particles. 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90% , About 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, or It is about 80% to about 90%.

[0081] In some embodiments, the shell comprises poly-L-lactic acid (PLLA) and the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% of the particles. ~ About 90%, about 20% ~ about 90%, about 25% ~ about 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% ~ about 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90% , Or about 80% to about 90%.

[0082] In some embodiments, the shell comprises poly (lactic acid-co-glycolic acid) (PLGA) and the polymer weight / weight is from about 5% to about 90% of the particles, from about 10% to about 90. %, About 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, About 45% to about 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75 % To about 90%, or about 80% to about 90%. The ratio of lactide: glycolide in the shell containing PLGA is about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40. : 60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85:15, about 90 : 10 or about 95: 5.

[0083] In some embodiments, the shell comprises a diblock or triblock copolymer in any combination of PCL, PLLA, PLGA or polyethylene glycol (PEG) and the polymer weight / weight is from about 5% of the particles. About 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90 %, About 40% to about 90%, About 45% to about 90%, About 50% to about 90%, About 55% to about 90%, About 60% to about 90%, About 65% to about 90%, It is about 70% to about 90%, about 75% to about 90%, or about 80% to about 90%.

[0084] In some embodiments, the shell comprises polyethylene glycol-diacrylate (PEGDA) and the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15 of the particles. % ~ About 90%, about 20% ~ about 90%, about 25% ~ about 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% ~ About 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90 %, Or about 80% to about 90%.

[0085] In some embodiments, the shell comprises a polyorthoester (POE) and the polymer weight / weight is from about 5% to about 90%, about 10% to about 90%, about 15% to the particles. About 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90 %, About 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, Or about 80% to about 90%.

[0086] In some embodiments, the shell is an aliphatic or aromatic polyanhydride, or an aliphatic-aromatic homopolyanhydride, such as poly (bis (P-carboxyphenoxy) methane (poly (CPM)),. Poly (1,3-bis (P-carboxyphenoxy) propane) (poly (CPP)), poly (1,6-bis (p-carboxyphenoxy) hexane) (poly (CPH)), poly (sevacinic acid anhydride) (Poly (SA)), poly (1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate), or poly (1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate) -co- It contains 1,4-bis (hydroxyethyl) terephthalate-co-terephthalate (P (BHET-EOP / BHET), 80/20), and the polymer weight / weight is about 5% to about 90% of the particles, about 10%. ~ About 90%, about 15% ~ about 90%, about 20% ~ about 90%, about 25% ~ about 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% to about 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90% , About 75% to about 90%, or about 80% to about 90%.

[0087] In some embodiments, the shell is diblocked with any combination of poly (bis (p-carboxyphenoxy) methane) (poly (CPM)) and poly (sebacic anhydride) (poly (SA)). Including copolymers, polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90 of the particles. %, About 30% to about 90%, About 35% to about 90%, About 40% to about 90%, About 45% to about 90%, About 50% to about 90%, About 55% to about 90%, It is about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, or about 80% to about 90%.

[0088] In some embodiments, the shell is any combination of poly (1,3-bis (p-carboxyphenoxy) propane (poly (CPP)) and poly (sebacic anhydride) (poly (SA)). Including diblock copolymers, the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% of the particles. ~ About 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% ~ about 90%, about 50% ~ about 90%, about 55% ~ about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, or about 80% to about 90%.

[0089] In some embodiments, the shell is any of poly (1,4-bis (p-carboxyphenoxy) butane) (poly (CPB)) and poly (sebacic anhydride) (poly (SA)). In combination with diblock copolymers, the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25 of the particles. % ~ About 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% ~ about 90%, about 50% ~ about 90%, about 55% ~ It is about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, or about 80% to about 90%.

[0090] In some embodiments, the shell is optional of poly (1,6-bis (p-carboxyphenoxy) hexane) (poly (CPH)) and poly (sebacic anhydride) (poly (SA)). In combination with diblock copolymers, the polymer weight / weight is about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25 of the particles. % ~ About 90%, about 30% ~ about 90%, about 35% ~ about 90%, about 40% ~ about 90%, about 45% ~ about 90%, about 50% ~ about 90%, about 55% ~ It is about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, or about 80% to about 90%.

[0091] In some embodiments, the shell and / or core further comprises a flocculant. In some embodiments, the flocculant is an alkyl cyanoacrylate monomer. Alkyl cyanoacrylate monomers include methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate, 2-octyl cyanoacrylate, and methoxyisopropyl cyanoacrylate. , Or a combination of these. The flocculant is about 0.2% to about 75%, about 0.3% to about 75%, about 0.4% to about 75%, about 0.5% to about 75% in the shell and / or core. , About 0.6% to about 75%, about 1% to about 75%, about 2% to about 75%, about 3% to about 75%, about 4% to about 75%, about 5% to about 75% , About 10% to about 75%, (g / g), about 15% to about 75%, about 20% to about 75%, about 25% to about 75%, about 30% to about 75%, about 35% ~ About 75%, about 40% ~ about 75%, about 45% ~ about 75%, about 50% ~ about 75%, about 55% ~ about 75%, about 60% ~ about 75%, about 65% ~ about 75%, about 70% to about 75%, about 0.2% to about 74%, about 0.2% to about 73%, about 0.2% to about 72%, about 0.2% to about 71% , About 0.2% to about 70%, about 0.2% to about 65%, about 0.2% to about 60%, about 0.2% to about 55%, about 0.2% to about 50% , About 0.2% to about 45%, about 0.2% to about 40%, about 0.2% to about 35%, about 0.2% to about 30%, about 0.2% to about 25% , About 0.2% to about 20%, about 0.2% to about 15%, about 0.2% to about 10%, or about 0.2% to about 5% w / w (aggregator / core polymer) Or it may be present in the proportion of flocculant / shell polymer).

[0092] Several mechanisms are involved in the rate and extent of colorant release. For very high molecular weight dyes, the rate of release is more dependent on the rate of bioabsorption of the vehicle. For dyes of lower molecular weight, the dye release rate is more dominated by diffusion. In either case, depending on the vehicle composition selected, ion exchange can also play a major role in the overall release profile.

[0093] In some embodiments, colorant release may exhibit a "delayed stage", decomposition is very slow or negligible, followed by rapid release of colorant. The particles of the invention are designed to be absorbed within a period of about 2 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 3 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 4 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 5 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 6 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 7 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 8 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 9 to about 12 months after administration. In some embodiments, the particles of the invention are designed to be absorbed within a period of about 10 to about 12 months after administration.

[0094] In some embodiments, the present disclosure is disclosed herein such that the composition prevents absorption of one or more colorants within a period of about 2 months to about 12 months. The present invention relates to a composition or a pharmaceutical composition containing a cosmetically effective amount of the composition of any one of the polymers or a combination thereof.

[0095] The tattoo ink itself can be a vehicle. The vehicle may be colored particles, which may optionally be physically or chemically modified to remain in the dermis indefinitely. Alternatively, these vehicles may be designed to dissolve spontaneously or be bioabsorbed and disappear after a predetermined period of time to form a semi-permanent tattoo. In other embodiments, these vehicles composed of dyes are heat, sound (ultrasonic), light (eg, laser light, infrared, or ultraviolet), electrical, magnetic, chemical, enzyme, mechanical, or any. It is such that it is sensitive to certain externally applied energy sources, such as other types of energy or combinations of energies. Treatment with the appropriate energy source of the tattooed skin allows the tattoo pigment to be sufficiently altered physically or chemically to eliminate it, and thus the tattoo can be erased as needed.

[0096] The particles can have any shape or size. For example, the particles are about 5 mm or less than 2 mm, or less than about 1 mm, or less than about 500 microns, less than about 200 microns, less than about 100 microns, less than about 60 microns, less than about 50 microns, less than about 40 microns, about 30 microns. It can have an average diameter of less than, less than about 25 microns, less than about 10 microns, less than about 3 microns, less than about 1 micron, less than about 300 nm, less than about 100 nm, less than about 30 nm, or less than about 10 nm. Preferably, the particles are less than about 100 microns.

[0097] The particles may be spherical or non-spherical. For example, the particles may be oval or elongated, or published as US Patent Application Publication No. 2008/0112886 on May 15, 2008, each of which is incorporated herein by reference. US Patent Application No. 11 / 851,974 filed on September 7, 2007, entitled "Engineering Shape of Polymeric Micro-and Nanoparticles" by Mitragotri et al .; International Publication No. 2008/031035 on March 13, 2008. Published as an issue, S. International Patent Application No. PCT / US2007 / 077889 filed on September 7, 2007, entitled "Engineering Shape of Polymeric Micro- and Nanoparticles" by Mitragotri et al .; US Patent Application Publication No. 2006 on September 14, 2006. Published as / 0213390, J.M. US Patent Application No. 11/272, 194 filed on November 10, 2005 under the name "Multi-phasic Nanoparticles" by Lahann et al .; or US Patent Application Publication No. 2007/0237800 on October 11, 2007. Published as J. Others, as disclosed in US Patent Application No. 11 / 763,842, filed June 15, 2007, entitled "Multi-Phasic Bioadhesive Nan-Objects as Biofunctional Elements in Drug Delivery Systems" by Lahann. It may have a shape. The average diameter of a non-spherical particle is the diameter of a perfect sphere having the same volume as the non-spherical particle. If the particles are non-spherical, they can have, for example, ellipsoids, cubes, fibers, tubes, rod shapes, or irregular shapes. In some cases, the particles may be hollow or porous. For example, core / shell structure (eg, with different composition), rectangular disc, high aspect ratio rectangular disc, high aspect ratio rod, worm, flat ellipse, oblong, UFO, circular disc, barrel, bullet, circle, pill, Pulley, biconvex lens, ribbon, labioli, flat pill, double cone, diamond disc, concave disc, elongated hexagonal disc, tacos, wrinkled oblong, wrinkled flat ellipse, porous elliptical disc, substantially Other shapes such as pyramid, conical or substantially conical are also possible.

[0098] As used herein, a "cosmetic effective dose," "cosmetic effective dose," or "cosmetic allowance" is the diet of a colorant in a subject for a predetermined period of about 1 to about 60 months or longer. Refers to an amount sufficient to prevent or inhibit the action. In some embodiments, the desired cosmetic effect depends on the tattooed design, or to the extent that the tattooed design is desired to be temporary. Thus, the cosmetic effect is associated with biodegradation, or release of the colorant from the particles, and / or inhibition of phagocytosis (partial or complete) of the particles upon administration to the subject, or exclusion from the subject's dermis. It can be a reduction in duration. A cosmetically effective amount can also be the amount required to reduce the toxicity or immunological response elicited after administration to a subject. In some embodiments, the immunological response can be determined based on the subject's age, health, size and gender. In some embodiments, the cosmetic effective amount can also be determined based on monitoring the subject's response to the treatment.

[0099] The term "subject" is used throughout the specification to describe an animal for which treatment with a composition according to the invention is provided or administered. The term "patient" may be used interchangeably for the treatment of conditions specific to a particular subject, such as a human. In some cases, in the description of the invention, the term "subject" will refer to a human subject. In some embodiments, the subject may be a mammal provided or administered with the present invention. In some embodiments, the subject may be a non-mammal to which the invention is provided or administered. In some embodiments, the subject is a domesticated mammal, such as a dog, horse, cat, pig, cow, rat, goat, sheep, or other domesticated mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a domesticated non-human livestock for which skin tagging or labeling is desired.

[00100] As used herein, the term "pigment disorder" refers to disorders associated with skin pigments (eg, melanin). Examples of pigment disorders include, but are not limited to, albinism, melasma, pigment loss after skin injury, melasma, and all forms of dysfunctional pigment secretion by any skin.

[00101] As used herein, "dosing" or "dosing" is any delivery to a subject of the composition used in the present invention in a manner that is cosmetically effective. Refers to the method. Preferably, the composition is administered to the dermis and / or epidermal layer of the skin.

[00102] The term "salt" refers to acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Examples of these acids and bases are well known to those of skill in the art. The salts according to the invention may be used in various forms, such as anhydrous or hydrated crystal forms. In some embodiments, the salt may be physiologically acceptable by the subject. In some embodiments of the invention, the term "salt" refers to one or more anhydrous compounds that find use in a laxative product according to the invention. The salts according to the invention can be found in their anhydrous form or in hydrate crystal form (ie, complexed or crystallized with one or more molecules of water). Suitable lowering salts for use in the present invention include, for example, monobasic, bibasic, and tribasic salts, or mixtures of monobasic, dibasic, and tribasic salts. Salts of active composition components are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the components of the invention contain relatively acidic functional groups, the base addition salt is such a compound in neutral form, either neat or in a suitable inert solvent, in sufficient quantity of the desired base. It can be obtained by contacting with. Pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. If the compounds of the invention contain relatively basic functional groups, the acid addition salt will bring such compounds in neutral form, either in a neat or suitable inert solvent, in a sufficient amount of the desired amount. It can be obtained by contact with an acid. Examples of pharmaceutically acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitrate, carbonic acid, monohydrogencarbonic, phosphoric acid, monohydrogenphosphoric, dihydrogenphosphoric. , Sulfuric acid, monohydrogensulfuric, derived from inorganic acids such as hydride or phosphite, as well as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid. , Suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other salts derived from relatively non-toxic organic acids. Be done. Also included are salts of amino acids such as alginate and salts of organic acids such as glucuronic acid or galactunophosphate (see, eg, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the invention include both basic and acidic functional groups capable of converting the compound into a base or an addition salt of an acid. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in the corresponding free base form, aqueous or other protic and aprotic solvents. In other cases, the preparation is a lyophilized powder in the pH range 4.5-5.5 in 1 mM-50 mM histidine, 0.1% -2% sucrose, 2% -7% mannitol. Possible, this is combined with buffer before use.

[00103] As used herein, the terms "treat," "treat," or "treat" are both therapeutic and prophylactic or preventative treatment. The purpose here is to prevent or slow down (alleviate) a physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of the present disclosure, beneficial or desired clinical outcomes are symptom relief; reduction of the degree of condition, disorder or disease; stabilization of condition, disorder or disease (ie, does not worsen); condition, disorder or Delayed or slowed progression of disease; improvement or remission (partially or wholly), detectable or undetectable of condition, disorder or disease condition; at least 1 not necessarily distinguishable by the patient Improvement of one measurable physical parameter; or including, but not limited to, enhancement or improvement of condition, disorder or disease. Treatment involves eliciting a clinically significant response without excessive levels of side effects. Thus, "treatment of pigmentation disorders" or "treatment of pigmentation disorders" prevents or alleviates either primary or secondary symptoms associated with pigment deficiency in a portion or area of the subject's skin. Or it means an activity to improve. In some embodiments, the symptom associated with pigment deficiency is a discoloration of the subject's skin that improves or changes upon administration of the compositions disclosed herein.

[00104] As used herein, the term "poly (N-isopropylacrylamide)" or "PNIPAM" is made from the monomers shown in Table 2 and their functionalized derivatives, as well as their functionalized derivatives of formula I. Means the polymer to be made.

式中、
Ｒ_１は、カルボキシ、ヒドロキシル、アミノ、又はＣ_１〜Ｃ_３０アルキル、アルケニル、アルコキシ、フェニル、シクロアルキル、フェノキシ、アリール、又はアルキルアミノであり；
Ｒ_２は、カルボキシ、ヒドロキシル、アミノ、又はＣ_１〜Ｃ_３０アルキル、アルケニル、アルコキシ、フェニル、シクロアルキル、フェノキシ、アリール、又はアルキルアミノである。いくつかの実施形態では、Ｒ_１及び／又はＲ_２は、独立して、Ｃ_１〜Ｃ_２５、Ｃ_１〜Ｃ_２０、Ｃ_１〜Ｃ_１５、Ｃ_１〜Ｃ_１０、又はＣ_１〜Ｃ_５アルキル、アルケニル、アルコキシ、フェニル、シクロアルキル、フェノキシ、アリール、又はアルキルアミノとして選択される。 [00105] N-Isopropylacrylamide can be copolymerized with, for example, methacrylic acid or acrylic acid and a di-acrylamide crosslinker to impart pH and / or temperature sensitivity.

During the ceremony
R ₁ is carboxy, hydroxyl, amino, or _C 1 _{-C 30} alkyl, alkenyl, alkoxy, phenyl, cycloalkyl, phenoxy, aryl, or alkylamino;
R ₂ is carboxy, hydroxyl, amino, or _C 1 _{-C 30} alkyl, alkenyl, alkoxy, phenyl, cycloalkyl, phenoxy, aryl, or alkyl amino. In some embodiments, R ₁ and / or R ₂ independently C _{1 to} C ₂₅ , C _{1 to} C ₂₀ , C _{1 to} C ₁₅ , C _{1 to} C ₁₀ , or C _{1 to} C ₅ It is selected as alkyl, alkenyl, alkoxy, phenyl, cycloalkyl, phenoxy, aryl, or alkylamino.

[00106] For clarity, it is further appreciated that the particular features of the present disclosure, described in the context of separate embodiments, may be provided in combination in a single embodiment. Conversely, for brevity, the various features of the present disclosure described in the context of a single embodiment may be provided separately or in any suitable subcombination.

[00107] The present disclosure uses, where applicable, the use of stereoisomers, diastereomers and optical stereoisomers of any one or more components of the particles described herein, as well as mixtures thereof. It is understood to include. Further, it is understood that the stereoisomers, diastereomers, and optical stereoisomers of the components of the present disclosure, as well as mixtures thereof, are within the scope of the present disclosure. As a non-limiting example, the mixture can include a colorant, a polymer, or a racemate of hydrogel, the mixture of which is one particular stereoisomer of one or more components in the particles. Can be included in unequal proportions to. In addition, the compounds can be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).

[00108] The components described herein can be asymmetric (eg, have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the present disclosure unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods of preparing optically active forms from optically active starting materials are known in the art, such as by splitting or stereoselective synthesis of racemic mixtures. Many geometric isomers such as olefins, CN double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are intended herein. To. Cis and trans geometric isomers of the compounds are also included within the scope of the present disclosure and can be isolated as a mixture of isomers or as a separated isomer form. If a compound capable of sterically or geometrically isomerized is specified in its structure or name without reference to a particular R / S or cis / trans configuration, all such isomers are intended. Intended.

[00109] The racemic mixture of compounds may be split by any of a number of methods known in the art, including fractional recrystallization using, for example, chiral splitting acids, which are optically active salt-forming organic acids. can. Suitable dividers for the fractional recrystallization method include tartaric acid, diacetyitartaric, dibenzoyliartane acid, mandelic acid, malic acid, optically active acids such as D and L forms of lactic acid, and β. -Various optically active camphor sulfonic acids such as, but not limited to, camphor sulfonic acid. Other partitioning agents suitable for fractional crystallization methods include stereoisomerically pure forms of-methyi-benzyl-arnine (eg, 5 and R forms, or diastereomerically pure). Morphology), 2-phenylglycinoi, norephedrine, ephedrine, N-methyiephedrine, cyciohexyleihylamine, 1,2-diaminocyclohexane and the like, but not limited to these. .. The racemic mixture can also be divided by elution on a column packed with an optically active dividing agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one of ordinary skill in the art.

[00110] Any one or more particle components may include tautomeric forms. The tautomeric form results from the transfer of protons and the exchange of adjacent double and single bonds at the same time. Tautomeric forms include prototropic tautomers in the isomer protonated state with the same empirical formula and total charge. Examples of prototropic tautomers are keto-enol pairs, amide-imide acid pairs, lactam-lactim pairs, amide-imide acid pairs, enamine-imine pairs, and 1H- and 3H-imidazoles, 1H-, 2H. -And 4HM, 2,4-triazole, 111- and 2H-isoindole, and a ring in which protons including, but not limited to, 1H- and 2H-pyrazole can occupy two or more positions in the heterocyclic system. The morphology is, but is not limited to, the tautomeric morphology can be in equilibrium by appropriate substitution or sterically locked into one morphology.

[00111] The particles of the present disclosure may contain hydrated and solvated forms of any component in the particles. For example, core polymers or hydrogels, matrix materials and colorants can be present in anhydrous and / or non-solvate forms. Ingredients can also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium.

[00112] In some embodiments, the compound or salt thereof is substantially isolated. The partial separation can include, for example, the colorants or particle-rich compositions of the present disclosure. Substantial separation is at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least. A composition containing about 99% by weight of the compound of the present disclosure or a salt thereof can be contained. Methods for isolating compounds or particles and their respective salts are routine in the art.

[00113] In some embodiments, the particles may be administered to the subject using a suitable carrier. For example, in one embodiment, the particles are administered by injection. The particles can be administered as a solution, suspension, or emulsion. Suitable carriers for injecting particles include sterile saline, phosphate buffered saline, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, etc. And oils such as vegetable oils, but are not limited to these. Formulations include dispersants, pH adjusters, buffers, surfactants, isotonics, preservatives, water soluble polymers (eg polyethylene glycol, polyvinylpyrrolidone, dextran, and carboxymethyl cellulose), temperature responsive polymers (eg, eg). One of poly (N-isopropylacrylamide) and its polymers, poly [2- (dimethylamino) ethyl methacrylate] (pDMAEMA), hydroxypropyl cellulose, poly (vinylcaprolactam) and polyvinylmethyl ether), and combinations thereof. It can contain the above pharmaceutically acceptable excipients. Water-soluble polymers, temperature-responsive polymers (eg, poly (N-isopropylacrylamide) and their copolymers, poly [2- (dimethylamino) ethyl methacrylate] (pDMAEMA), hydroxypropyl cellulose, poly (vinyl caprolactam) and polyvinylmethyl Ether) is about 0.1% to about 50%, about 0.2% to about 50%, about 0.3% to about 50%, about 0.4% to about 50%, about 0.5% to. About 50%, about 1% to about 50%, about 2% to about 50%, about 0.1% to about 50%, about 3% to about 50%, about 4% to about 50%, about 5% to About 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 35% to about 50 %, About 40% to about 50%, About 45% to about 50%, About 0.1% to about 49%, About 0.1% to about 48%, About 0.1% to about 47%, About 0 .1% to about 46%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0 .1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0 .Be present in the carrier in the range of 1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1% w / v. Can be done.

[00114] In another embodiment, the particles may be administered topically to the surface of the subject's skin or mucous membrane using a suitable carrier. Suitable carriers for topical administration of particles include gels, foams, ointments, pastes, and lotions. The cream or lotion can contain, for example, emulsions of hydrophobic and hydrophilic materials (eg, oil and water) distributed in any order (eg, oil in water or water in oil), and the particles are: It can be present in any one or more of the emulsion phases.

[00115] As used herein, "carrier solution" may refer to any of the suitable carriers listed above. In some embodiments, the carrier solution is on the outside of the particles or composition of the invention. In some embodiments, the carrier solution is in the particles or composition of the invention. For example, the carrier solution may be placed between layers of particles.

[00116] As used herein, "hydrophilic" refers to a substance with a strong polar group that easily interacts with water.

[00117] As used herein, "hydrophobic" refers to a substance that lacks an affinity for water, tends to repel and not absorb water, and is insoluble or immiscible with water.

[00118] "Continuous phase" refers to a liquid in which a solid is suspended or droplets of another liquid are dispersed, sometimes referred to as an external phase. It also refers to the colloidal fluid phase in which solid or fluid particles are distributed therein. If the continuous phase is water (or another hydrophilic solvent), the water-soluble or hydrophilic drug dissolves in the continuous phase (as opposed to being dispersed). In a polyphase formulation (eg, an emulsion), the inconspicuous phase is suspended or dispersed in the continuous phase.

[00119] An "emulsion" is a composition containing a mixture of immiscible components that are homogeneously blended together. In certain embodiments, the immiscible component comprises a lipophilic component and an aqueous component. An emulsion is a preparation of one liquid distributed in small globules throughout the body of the second liquid. The dispersion is a discontinuous phase and the dispersion medium is a continuous phase. If the oil is a dispersion and the aqueous solution is a continuous phase, this is known as an oil-in-water emulsion, while if the water or aqueous solution is a dispersed phase and the oil or oily substance is a continuous phase, this is an oil. Known as medium water emulsion. Either or both of the oil and aqueous phases may include one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially nonionic surfactants; emulsifiers, especially emulsified waxes; and liquid non-volatile non-aqueous substances, especially glycols such as propylene glycol. The oil phase may contain other oily, pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil can be used in the oil phase as a surfactant or emulsifier.

[00120] A "lotion" is a low to medium viscosity liquid formulation. Lotions can contain fine powder substances that are soluble in the dispersion medium through the use of suspending and dispersants. Alternatively, the lotion can have a liquid substance as the dispersed phase, which is immiscible with the vehicle and is usually dispersed by an emulsifier or other suitable stabilizer. The fluidity of the lotion allows for rapid and uniform application over a large surface area. Lotions are typically intended to dry on the skin, leaving a thin coating of those pharmaceutical ingredients on the surface of the skin.

[00121] A "cream" is a viscous liquid or semi-solid emulsion of either "oil-in-water" or "water-in-oil". The cream may contain emulsifiers and / or other stabilizers. In one embodiment, the formulation is in the form of a cream having a viscosity greater than 1000 centi-stokes, typically in the range of 20,000-50,000 centi-stokes. Creams are often preferred over ointments because they are generally easier to spread and easier to remove.

[00122] The difference between a cream and a lotion is the viscosity, which depends on the amount / use of the various oils and the proportion of water used to prepare the formulation. Creams are typically thicker than lotions and can have a variety of uses, often using a wider variety of oils / butters, depending on the desired effect on the skin. In the cream formulation, the water-base ratio is about 60-75% of the total, the oil-base ratio is about 20-30%, and the other ratios are 100% in total. Emulsifiers, preservatives and additives contained.

[00123] An "ointment" is a semi-solid preparation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases are hydrocarbon bases (eg petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water removable. Bases (eg, hydrophilic ointments); and water-soluble bases (eg, polyethylene glycol ointments). Pastes typically differ from ointments in that they contain a higher percentage of solids. Pastes are typically more absorbent and less greasy than ointments prepared with the same ingredients.

[00124] A "gel" is a semi-solid containing a small or large dispersion in a liquid vehicle that has been made semi-solid by the action of a thickener or polymer material dissolved or suspended in the liquid vehicle. It is a system. The liquid can contain a lipophilic component, an aqueous component, or both. Some emulsions may be gels or may contain gel components otherwise. However, some gels are not emulsions as they do not contain a uniform blend of immiscible ingredients. Suitable gelling agents include, but are not limited to, modified celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol® homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alkylene (alklene) glycols such as propylene glycol; dimethyl isosorbide; alcohols such as isopropyl alcohol and ethanol. The solvent is typically selected by its ability to dissolve the drug. Other additives that improve the skin feel and / or emollientity of the formulation may also be incorporated. Examples of such additives include, but are not limited to, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oils, squalane, cyclomethicone, capric acid / caprylic acid triglycerides, and combinations thereof.

[00125] As used herein, a "hydrogel" is a three-dimensional open lattice structure in which an organic polymer (natural or synthetic) is cured or solidified to capture water or other solution molecules to form a gel. Is defined as the substance formed when producing. Solidification can occur, for example, by agglutination, coagulation, hydrophobic interactions, or cross-linking.

[00126] The foam consists of an emulsion combined with a gaseous propellant. The gaseous propellant mainly consists of hydrofluoroalkane (HFA). Suitable propellants include HFA such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227). Appropriate are mixtures and admixtures of these and other HFAs that are currently approved or can be approved for medical use. The propellant is preferably not a hydrocarbon propellant gas capable of producing flammable or explosive vapors during spraying. In addition, the composition preferably does not contain volatile alcohols that can produce flammable or explosive vapors during use.

[00127] The buffer is used to control the pH of the composition. Preferably, the buffer has a pH of composition ranging from about 4 to about 7.5, more preferably from about 4 to about 7 pH, most preferably from about 5 to about 7. Maintain at pH. In a preferred embodiment, the buffer is triethanolamine.

[00128] Preservatives can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antibacterial agents include benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol. , Phenol, phenylethyl alcohol, and thimerosal, but are not limited thereto.

[00129] Alternatively, the particles may be mucosal adhesive or sprayed onto the mucosal surface of the tissue. For example, the particles may be formed from a mucosal adhesive polymer. Mucosal adhesive polymers can be divided into two groups: hydrogels and hydrophilic polymers. Mucosal adhesive polymers typically contain functional groups that adhere to the tissue, such as carboxylic acid groups, hydroxyl groups, and / or amine groups. Classes of mucosal adhesive polymers include polyvinylpyrrolidone (PVP), methylcellulose (MC), sodium carboxymethylcellulose (SCMC) hydroxypropylcellulose (HPC) and other cellulose derivatives, carbopols, polyacrylates and crosslinked polyacrylates, chitosan and Examples include, but are not limited to, derivatives thereof (N-trimethylchitosan), acrylic resins, available under the trade name Eudragits®, poly (dimethyl-aminoethyl methacrylate) (PDMAEMA), and combinations thereof.

[00130] In some embodiments, the carrier solution comprises a stabilizer. As used herein, "stabilizer" refers to a substance that, when added to a polymeric material, prevents or slows down the decomposition process. See, for example, Concise Chemical and Technical Dictionary, Fourth Enlarged Edition, Bennet, Chemical Publishing Co., NY, N.Y. (1986).

[00131] In some embodiments, the composition further comprises a biocide. As used herein, a "biocide" is any compound that inhibits or prevents the growth of a pathogen. In some embodiments, the biocide is an antibiotic. In some embodiments, the composition is amikacin, anisomycin, apramycin, azithromycin, blastomycin S, brefelzin A, butyrosine, chloramphenicol, chlortetracycline, clindamycin, clotrimazole, cycloheximide, deme. Demeclocycine, dibecacin, dihydrostreptomycin, doxicycline, duramycin, emetin, erythromycin, fucidic acid, G438, gentamicin, helboric acid, hyglomycin B, josamicin, kanamycin, kilomycin, lincomycin, meclocycline, mepartricin, Midecamycin, minocycline, neomycin, netylmycin, noseoslycin, oleandomycin, oxytetraeycline, paromomycin, puromycin, rapamycin, ribostamycin, rifampicin, rifamiein, rosamicin, cisomycin, spectinomycin, streptomycin. , Streptomycin, Tetracycline, Thiaphenicol, Thiostrepton, Tobramycin, Tunicamycin, Tyrosine, Bleomycin, Virginiamycin, Camptothecin, 10-Deacetylbaccatin III, Azacitidine, 7-Aminoactinomycin D, 8-Kinolinol, 9- Dihydro-1,3-acetylbaccin III, acralubicin, actinomycin D, actinomycin I, actinomycin V, bafilomycin A1, bleomycin, caprecmycin, chromomycin, cinoxacin, cyprofluxacin, cis- Diamine Platinum (ii) Dichloride, Coumamycin A1, L (+)-Lactic Acid, Cytocarasin B, Cytocarasin D, Dacarbazine, Daunorubicin, Distamicin A, Doxorubicin, Ekinomycin, Enlofloxacin, Etopocid, Flumekin, Formycin, gancyclovir, metronidazole, mythromycin A, mitomycin C, naridixic acid, nogalamycin, nonactin, novobiocin, offluxacin, oxolinic acid, paclitaxel, phenazine, freomycin, rebeccamycin, cinefangin, streptomycin, streptomycin, succinyl Sulfaziazine, su Rufadimethoxyn, sulfaguanidineplum, sulfamethazine, sulfamonomethoxyn, sulfanylamide, sulfaquinoxalin, sulfasalazine, sulfatiazole, trimetoprim, tubersidin, 5-azacitidin, formycin A, (+)-6-aminopenicillic acid , 7-Aminodesacetoxycephalosporanic acid, amoxycillin, ampicillin, azurosylin, bacitracin, carbenicillin, cefaclor, cefamandol, cefazoline, cefmethazole, cefoperazone, cefotaxim, cefthrosin, ceftriaxone, cephaloxin, cephalosin , Croxacillin, D-Cycloserine, Dicloxacillin, D-Penicilamine, Econazole, Etambutol, Rizostafin, Moxalactam, Nafcillin, Nikkomycin Z, Nitrofrantoin, Oxacilin, Penicillin G, Pheneticillin, Phenoxymethylpenicillinic acid, Phosomycin, Pipemidic acid , Listmycin, bacitracin, 2-mercaptopyridine, 4-bromocalcimycin A23187, alamethicin, ampicillin B, calsimycin A23187, chlorhexidine, colistin, hydrocortisone, Philippines, gliotoxin, gramicidin A, gramicidin D, ionomycin, lasaroside A, lanomycin. , Monencin, N- (6-aminohexyl) -5-chloro-1-naphthalene sulfonamide, lanacin, nigericin, nycin, nistatin, pimalysin, polymyxin B, DL-penicillamine, polymyxin E, prazicantel, salinomycin, surfactin, valinomycin , (+)-Usnic acid, myconazole, 1-deoxymannodirimycin, 2-heptyl-4-hydroxyquinolin-oxide, cordisepine, 1,10-phenanthroline, 6-diazo-5-oxo-L-norleucin, antimycin , Antipine, ascomycin, azaserine, bacitracin, cerulenin, chloroquin, mevastatin, concanamycin A, concanamycin C, cyclosporin A, frazolidone, fusalic acid, geldanamycin, gramicidin C, harbimycin A, indomethacin, romefloxacin, Mycophenolic acid, mixothiazole, netropsin, niclosamide, kanamycin, Methyl-deoxynolirimycin, oligomycin, pierisidine A, radisicol, staulosporin, stigmaterin, sulfaguanidine, triaxin C, paraceisin, rifalexin, lolacarbef, eltapenem, dripenem, imipenam, cilastatin ), Meropenem, cefadoroxyl, cefalotin, cefalothin, cefoxytin, cefprodil, cefloxim, cephalexin, cefzinyl, cefdithren, cefpodoxim, ceftazidime, ceftibulene, ceftibulen, ceftibulen, ceftibulen , Teicopianin, telavanein, daptomycin, clarislomycin, dilithromycin, loxythromycin, gachifloxacin, levofloxine, moxifloxacin, norfloxacin, trovailoxacin, grepafloxacin , Sparfloxacin, Temafloxacin, Maphenide, Sulfacetamide, Silver suladiazine, Sulfamethoxazole, Sulfamethoxazole, Sulfisoxazole, Sulfonam idochrysoidine, Clofadimin, Dapson, Ethionamide, isoniazide, pyrazinamide, rifabutin, rifapentine, arsphenamine, phosphomycin, mupiroein, platensimycin, quinupristin, dalhopristin, tigecycline, ceftazidime, tinidazoie, artemicinin, mate It further comprises an antibacterial agent selected from sulfadoxine-pyrimetamine, hydroxychlorokin, amodiakin, pyrimetamin, sulfadoxine, proguanyl, meropenem, atobacon, primakin, and halophanthrin. In any of the above embodiments, the antibacterial agent is selected from gentamicin, imipenum, piperacillin, ceftazidime, aztreonam, ceftriaxone, ampicillin, ciprofloxacin, linezolid, daptomycin, and rifampicirs. In some embodiments, the antibacterial agent is anisomyein, apramycin, blastomycin S, brefelzin A, butyrosine, chlortetracycline, clotrimazole, cycloheximide, demeclocycline, dibecasin, dihydrostreptomycin, duramycin, emetin, Fusidic acid, G438, helboric acid, hyglomycin B, kanamycin, kilomycin, lincomycin, mecrocycline, mepartricin, midecamicin, netylmycin, nitrofurantoin, noseosuricin, oleandomycin, paromomycin, puromycin, rapamycin, ribostamicin , Rifampicin, Rifamycin, Rosamicin, Spectinomycin, Spiramycin, Streptomycin, Thianphenicol, Camptothecin, 10-Deacetylbaccatin III, Azacitidine, 7-Aminoactinomycin D, 8-Kinolinol, 9-Dihydro-1, 3-Acetylbaccin III, acralubicin, actinomycin D, actinomycin I, actinomycin V, bafilomycin A1, bleomycin, capreomycin, chromomycin, cinoxacin, cyprofluxacin, cis-diamine platinum (ii) dichloride , Coomamycin A1, L (+)-Lactic acid, Cytocarasin B, Cytocarasin D, Dacarbazine, Daunorubicin, Distamicin A, Doxorubicin, Echinomycin, Enlofloxacin, Etopocid, Flumekin, Hormycin, Fumagillin, Gancyclovir, Glyotoxin , Metronidazole, Misramycin A, Mitomycin C, Nalidixic acid, Netropsin, Nitrofurantoin, Nogalamycin, Nonactin, Novobiosin, Oxolinic acid, Paclitaxel, Phenazine, Freomycin, Pipemidic acid, Rebeccamycin, Cinefangin, Streptomycin, Streptomycin, Streptomycin Sulfatiazole, sulfaziazine, sulfadimethoxyn, sulfaguanidine plum, sulfamethazine, sulfamonomethoxyn, sulfanilamide, sulfakinoxalin, sulfasalazine, sulfatiazole, tubercidine, 5-azacitidine, cordisepine, streptomycin A, (+) -6 -Aminopenicanic acid, 7-Aminodesacetoxycephalosporanic acid, Amoxycillin, Ampici Phosphorus, azlocillin, bacitracin, carbenicillin, cefaclor, cefamandol, cefazoline, cefmethazole, cefotaxim, cefthrosin, cephalexin, cephalosporin C, cephalotin, cefladine, cloxacillin, D-cycloserine, dicloxacillin, D-penicillin Rizostaffin, moxifloxacin, naphthylin, nikkomycin Z, nitrofurantoin, oxacillin, penicillic, penicillin G, pheneticillin, phenoxymethylpenicillic acid, phosphomycin, pipemidic acid, piperacillin, wristomycin, bacitracin, 2-mercaptopyridine, 4- Bromocalcycin A23187, alamethicin, amphotelicin B, kanamycin A23187, chlorhexidine, clotrimazole, econazole, hydrocortisone, Philippines, gliotoxin, gramcidin A, gramicidin C, ionomycin, lasalocid A, lonomycin A, onensin. , N- (6-aminohexyl) -5-chloro-1-naphthalene sulfonamide, ranacin, nigericin, nycin, nistatin, phenazine, pimalysin, DL-penicillin, prazicantel, kanamycin, 2-heptyl-4-hydroxyquinolone N- Oxide, 1,6-diazo-5-oxo-L-norleucin, 8-quinolinol, antimycin, antipine, ascomycin, azaserin, bacitracin, cerulenin, chlorokin, cinoxacin, mevasatin, concanamycin A, concanamycin C , Coumamycin A1, Cyclosporin A, Furazolidone, Radicicol, Rapamycin staurosporin, Sulfaguanidine, Triaxin C, Trimethoprim, Cilastatin, Melopenem, Cefalexin, Levofloxacin, Moxifloxacin, Trovafioxaein , Grepafloxacin, sparfioxacin, temafloxacin, sulfamethizole, sulfamethoxazole, sulfonamidechrysoidine, clofazimin, dapson, etionamide, isoniazide, pyrazinamide, rifabtin, Rifapentine, Arsphenamine, Fosfomycin, Mupirocin, Quinine, quinuprislin, dall pristin, Tigecycline, Imidazole, Artemistin, Artesunate, Quinine, Sulfadoxine-pyrimetamine, Hydroxychloro Quinine, Amodiaquine,
It is selected from sulfadoxine, proguanil, mefloquine, atovaquone, primaquine, and haloofantrine. In some embodiments, the antibacterial agent is selected from one or a combination of imipenum, piperacillin, aztreonam, ampicillin, linezolid, daptomycin, and rifampicin.

[00132] The amount of antibacterial agent can be determined based on known dosages, and in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of antibacterial agent. In some embodiments, the amount of antibacterial agent in the pharmaceutical composition having the arylaniide compound is about 10%, about 20%, about, as compared to when the antibacterial agent is administered alone. It can be reduced by 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.

[00133] In some embodiments, the composition further comprises a moisturizer. As used herein, "moisturizer" refers to any substance that promotes water retention. Suitable moisturizers include polyhydric alcohols or glycerin. Other suitable moisturizers include polyhydric alcohols such as ethylene glycol, propylene glycol, triethylene glycol, tetraethylene glycol, and sorbitol.

[00134] Any particle, carrier solution, or composition disclosed herein can be an ingredient in a pharmaceutical composition. In any such pharmaceutical composition, the composition comprises a pharmaceutically effective amount of one or more disclosed compositions and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises nanoparticles comprising one or more disclosed compositions in a pharmaceutically effective amount. In some embodiments, the nanoparticles are polymer-containing nanoparticles in a homogeneous or heterogeneous mixture, so if the mixture is homogeneous, the nanoparticles are the same or substantially the same disclosed herein. Contains the composition. In a heterogeneous mixture, the pharmaceutical composition comprises a plurality of nanoparticles, the plurality of nanoparticles comprising different compositions disclosed herein within or among some of the particles.

[00135] According to the present invention, improved tattoo inks are provided by incorporating conventional tattoo dyes (eg, Indian inks) into the vehicle, the incorporation of which is their size, adhesion to dermal elements, or. It yields a pigment / vehicle complex that remains in the dermis due to cellular encapsulation. In this embodiment of the invention, the tattoo ink produces a permanent tattoo with clear lines by capturing the diffusible dye particles into larger non-diffusible aggregates. The material used in the vehicle to make a permanent tattoo ink is a substance that has the physical properties necessary to remain in the dermis indefinitely. These vehicle materials are suitable for the production of permanent tattoos, where all pigment / vehicle complexes have a sufficiently large size so that the tattoo design is not blurred by the diffusion of the pigment into the adjacent dermis. used. When the tattoo ink contains only the optimal size, generally about 10 to about 999 nanometers of dye particles, there is less blurring of the tattoo lines and the dye does not partially fade or diffuse into adjacent tissue and from the dermis. Not excluded.

[00136] Alternatively, the vehicle can bind to skin elements such as collagen, elastin, glycosaminoglycans, etc. via ions, covalent bonds, or other molecular mechanisms. Binding factors include fibronectin, laminin, vitronectin, fibrinogen, fibrin, intercellular adhesion molecule-1, and various identified adhesion peptide sequences such as arginine, glycine, aspartic acid sequence (RGD), and other peptides. It includes, but is not limited to, natural adhesion molecules such as sequences (YIGSR and the like) or synthetic adhesives such as cyanoacrylate.

[00137] The term "carrier" includes a pharmaceutical carrier or "excipient" and, as used herein, any and all solvents, dispersion media, suitable for the desired particular composition form. Includes diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonics, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Remington's The Science and Practice of Pharmacy, 21st Edition, AR Gennaro, (Lippincott, Williams & Wilkins, Baltimore, Md., 2006) is a variety of excipients used in the preparation of pharmaceutical compositions and for their preparation. The known technology is disclosed. Any conventional excipient with a substance or derivative thereof, for example by producing an unwanted biological effect or interacting with any other component of the pharmaceutical composition in a detrimental manner. Its use is intended to be within the scope of the invention, except in cases of nonconformity. The compositions described herein are solutions, suspensions, emulsions, tablets, tablet coatings containing other active agents, microcapsules, pellets, capsules, liquid-containing capsules, powders, sustained release formulations. , Suppository, aerosol, spray form, or any other form suitable for topical use. In some embodiments, the compositions disclosed herein include a gel formulation having one or more excipients that are not bioactive and do not react with the active compound. Excipients for tablets may include fillers, binders, lubricants and flow promoters, disintegrants, wetting agents, and release rate modifiers. The binder promotes the adhesion of the particles of the formulation and is important for the tablet formulation. Examples of binders include carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, Karaya gum, starch, starch, and tragant gum, polyfacrylic acid, and polyvinylpyrrolidone. Not limited. Topical formulations containing 3-methanesuifonylpropionitrile can be the formation of gels, creams, lotions, liquids, emulsions, ointments, sprays, solutions, suspensions, and patches. Examples of the inert component in the topical preparation include lauryl lactate (skin softener / penetration enhancer), diethylene glycol monoethyl ether (skin softener / penetration enhancer), DMSO (solubility enhancer), and silicone elastomer (leology /). Texture modifier), capric acid triglyceride, (skin softener), octisalate, (skin softener / UV filter), silicone fluid (skin softener / diluent), squalane (skin softener), sunflower oil 1 (skin softening) Agent) and silicone dioxide {thickener), but are not limited thereto.

[00138] In some embodiments, the pharmaceutically acceptable excipient or carrier is at least 95%, 96%, 97%, 98%, 99%, or 100% pure. In some embodiments, the excipient is approved for use in humans and for veterinary use. In some embodiments, the excipient is approved by the United States Food and Drug Administration. In some embodiments, the excipient is pharmaceutical grade. In some embodiments, the excipient meets the standards of the United States Pharmacopeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia, and / or International Pharmacopoeia, which is incorporated herein in its entirety. There is.

[00139] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders. Agents, preservatives, buffers, lubricants, and / or oils include, but are not limited to. Such excipients may optionally be included in the formulations of the present invention. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavoring agents, and fragrances may be present in the composition at the discretion of the preparer.

[00140] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium lactose phosphate, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol. , Inositol, sodium chloride, dried starch, corn starch, powdered sugar and the like, and combinations thereof, but are not limited thereto.

[00141] Exemplary granulation and / or dispersants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges. , Cationic exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly (vinylpyrrolidone) (crosspovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (crosscarmellose), Examples thereof include methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof. Not limited to.

[00142] Exemplary surfactants and / or emulsifiers include natural emulsifiers (eg, acacia, agar, alginic acid, sodium alginate, traganth, condorx, cholesterol, xanthane, pectin, gelatin, egg yolk, casein, wool fat, etc. Colloidal clay (eg, bentonite [aluminum silicate] and Veegum [magnesium silicate]), long chain amino acid derivatives, high molecular weight alcohols (eg, stearyl alcohol, cetyl alcohol, oleyl alcohol, etc.) Triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomer (eg, carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan. , Cellulose derivatives (eg, sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose), sorbitan fatty acid esters (eg, polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [ Tween 60], Polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan mono Oleate [Span 80]), polyoxyethylene esters (eg, polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylyylated castor oil, polyoxymethylene stearate, and Solutol), Sculose fatty acid ester, polyethylene glycol fatty acid ester (eg Cremophor), polyoxyethylene ether (eg polyoxyethylene lauryl ether [Brij 30]), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, Sodium oleate, potassium oleate, ethyl oleate, oleate, ethyl laurate, lauryl sulphate Sodium acid, Pluronic F 68, Pluronic® F 127, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, sodium doxart, etc., and / or combinations thereof. Not limited.

[00143] Exemplary binders include starch (eg, corn starch and starch paste); gelatin; sugar (eg, sucrose, glucose, dextrose, dextrin, honey, lactose, lactitol, mannitol); natural and synthetic rubber (eg, mannitol). , Acacia, sodium alginate, Irish moss extract, panwar gum, gatch gum, isapol shell mucilage, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-) Pyrrolidone), magnesium aluminum silicate (Vegum), and lattice labogalactan); alginate; polyethylene oxide; polyethylene glycol; inorganic calcium salt; silicic acid; polymethacrylate; wax; water; alcohol; etc.; and combinations thereof. However, it is not limited to these.

[00144] One aspect of the present disclosure relates to a composition comprising particles of either homogeneous or heterogeneous species in a non-aggregated form at room temperature or at about 65 to about 75 ° F. In some embodiments, the composition comprises particles of either homogeneous and / or inhomogeneous species in non-aggregate form at room temperature or about 65 to about 75 ° F, but at body temperature or about 98 to about 100 ° F. When exposed to the specimen in, the particles aggregate. Note that agglutination and non-aggregation of particles may not be induced by exposure of the particles to the sample. In another set of embodiments, for example, the clustering or agglomeration properties of the particles are controlled externally in some way. For example, electrical, magnetic, and / or mechanical forces can be used to bring the particles closer to each other and / or separate the particles. Thus, in some cases, by applying electrical, magnetic, and / or mechanical forces to the particles, the particles show a color change upon administration and / or increase the rate of dispersion. The clustering or agglomeration of particles as discussed herein is generally not limited to spherical agglomeration. In some cases, the particles can be clustered on the surface, or the particles can be aligned to the surface in some way due to the sample or other external force.

[00145] Further, it should be noted that the particles may contain reaction entities that are not necessarily binding partners to the sample. For example, there may be a first layer containing a first reaction entity and a second layer or cavity containing a second reaction entity that reacts with the first reaction entity, the particles or contents of the cavity. Of electrical, magnetic, and / or mechanical forces that bring the particles closer together in some way (eg, by exposure to a sample or other chemical that is recognized by a binding partner on each particle. The first and second reaction entities may react when combined (by application, biodegradation, etc.). As a particular example, the reaction between the first reaction entity and the second reaction entity may be an endothermic reaction or an exothermic reaction, so that when the particles are put together, a temperature change occurs, which causes a temperature change. Can be determined in some way. As another example, the reaction between the first and second reactants can cause the release of material. In some cases, the material can be a material that can be perceived by the subject, such as capsaicin, acids, allergens and the like. Therefore, the subject can perceive changes as changes in temperature, pain, itchiness, swelling and the like. In some embodiments, exposure of the first and second reaction entities chemically modifies the colorant so that the color of the design can change.

[00146] In some cases, the particles may be suspended in a carrier fluid, eg, physiological saline, or the particles may be accessible or accessible by a matrix, eg, interstitial fluid after delivery. It may be contained in a porous matrix, a hydrogel matrix, or the like. For example, the matrix may be formed from biodegradable and / or biocompatible materials such as polylactic acid, polyglycolic acid, poly (lactic-co-glycolic acid), or other similar materials.

[00147] In some cases, the matrix prevents the subject's immunological response to the presence of the particles, while allowing equilibration of the specimen, etc. with the particles, for example when the matrix is porous. Or at least can be inhibited. For example, the pores of the porous matrix may be such that they cannot penetrate immune cells, but can penetrate proteins, small molecules (eg, glucose, ions, dissolved gas, etc.). The pores are, for example, less than about 5 micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1.5 micrometers, less than about 1.0 micrometer, about 0.75. Less than micrometer, less than about 0.6 micrometer, less than about 0.5 micrometer, less than about 0.4 micrometer, less than about 0.3 micrometer, less than about 0.1 micrometer, about 0.07 micrometer Less than, in other embodiments, or less than about 0.05 micrometer. The matrix may include, for example, biocompatible and / or biodegradable polymers such as polylactic acid and / or polyglycolic acid, polyan anhydride, polycaprolactone, polyethylene oxide, polybutylene terephthalate, starch, cellulose, chitosan, and / or. These combinations and / or other materials may be included, such as agarose, collagen, fibrin and the like.

[Method]
[00148] Embodiments of the present disclosure relate to a method of administering the compositions and pharmaceutical compositions of the present disclosure. The particles can be administered by a typical tattoo device to deliver the particles to the dermis of the subject. The procedure for marking tissue is traditionally a needle or similar instrument to introduce an ink that is suspended in a liquid carrier and typically contains inert and insoluble dye particles with a wide distribution size. Consists of perforating the skin with. Examples of devices typically used to apply tattoos are electromagnetic coil tattoo devices (such as those disclosed in US Pat. No. 4,159,659 to Nightingale), rotary permanent cosmetic application devices. (The one disclosed in US Pat. No. 5,472,449 to Chou, etc.), or any manual tattoo device (such as a sterile single-use device marketed by Softap Inc. of San Leandro, Calif.) ) Is included.

Polymer microspheres encapsulated in dyes / dyes are available in a wide range of methods: solvent evaporation in emulsions, phase separation, core selvation, spray drying, cross-linking / gelling, hot melt, grinding, electrospraying, and polymerization. Can be prepared using (emulsion, suspension, dispersion, and precipitate). In polymerization techniques, the starting material is an unsaturated monomer molecule, which forms beads during chain polymerization. In all other techniques described below, the starting material is already a polymer.

[00150] Emulsion. There are two types of single emulsion technology: oil-in-water type (o / w) and water-in-oil emulsion (w / o). For example, natural polymer particulate carriers, ie protein and carbohydrate particulate carriers, are prepared by these single emulsion techniques. The natural polymer is dissolved or dispersed in an aqueous medium and subsequently dispersed in a non-aqueous medium such as oil. In the next step, cross-linking of dispersed globules is performed. Cross-linking can be achieved by UV or heat, or by using chemical cross-linking agents. The chemical cross-linking agents used are glutaraldehyde, formaldehyde, acid chlorides and the like. The nature of the surfactant used to stabilize the emulsion phase can significantly affect the size, size distribution, surface morphology, loading, dye / dye release, and bioperformance of the final multiparticle product.

[00151] The double emulsion method for microsphere preparation involves the formation of multiple emulsions or w / o / w type double emulsions and is most suitable for water soluble dyes / dyes. This method can be used with both natural and synthetic polymers. The dye / aqueous dye solution is dispersed in the lipophilic organic continuous phase. The continuous phase generally consists of a polymer solution that ultimately encapsulates the dye / dye contained in the dispersed aqueous phase. The primary emulsion is then homogenized or sonicated prior to addition to the aqueous solution of polyvinyl alcohol (PVA). As a result, a double emulsion is formed. The emulsion is then subjected to solvent removal by either solvent evaporation or solvent extraction.

[00152] Spray drying. In the spray drying technique, the polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. The dye / dye in solid form is then dispersed in the polymer solution using fast homogenization. The dispersion is then atomized in a hot air stream. Atomization results in the formation of small droplets or fine mists from which the solvent evaporates instantaneously, resulting in the formation of microspheres in the size range of 200 nm to 100 μm. The size can be manipulated by modifying some parameters such as polymer concentration, solution flow rate, spray rate, and drying temperature. The fine particles are separated from the hot air by a cyclone separator, while trace amounts of solvent are removed by vacuum drying. One of the main advantages of this process is the feasibility of the operation under sterile conditions.

[00153] Solvent evaporation. This process takes place in the liquid manufacturing vehicle phase. The microcapsule coating is dispersed in a volatile solvent that is immiscible with the liquid production vehicle phase. The microencapsulated core material (dye / dye) is dissolved or dispersed in the coated polymer solution. Upon agitation, the core material mixture is dispersed in the liquid production vehicle phase to give microcapsules of appropriate size. The mixture is then heated, if necessary, to evaporate the solvent for the polymer of the core material dispersed in the polymer solution, causing the polymer to shrink around the core. When the core material is dissolved in a coated polymer solution, matrix-type microcapsules are formed. The core material may be either a water-soluble material or a water-insoluble material. Solvent evaporation involves the formation of an emulsion between the polymer solution and an immiscible continuous phase (whether aqueous (o / w) or immiscible).

[00154] Phase separation core selvation technology. This process is based on the principle of reducing the solubility of the polymer in the organic phase in order to affect the formation of the polymer-rich phase called coacervates. In this method, the dye / dye particles are dispersed in a solution of the polymer and an incompatible polymer is added to the system, which causes the first polymer to be phase separated and the dye / dye particles incorporated. Addition of non-solvent results in solidification of the polymer. Polylactic acid (PLA) microspheres have been prepared in this way by using butadiene as an incompatible polymer. Process variables are very important because the rate at which the coacervate is achieved determines the distribution of the polymer film, the particle size and agglomeration of the particles formed. Aggregation must be avoided by stirring the suspension with a suitable speed stirrer. This is because as the process of microspherical morphology begins, the morphed polymerized globules begin to adhere and form aggregates. Therefore, process variables are important for controlling the kinetics of the formed particles, as there is no defined state of reaching equilibrium.

[00155] Solvent extraction. The production of dye / dye-containing micros uses solvent evaporation and involves removal of the organic phase by extraction of a non-aqueous solvent. This method comprises a water-miscible organic solvent as isopropanol. The organic phase can be removed by extraction with water. This process reduces the curing time of microspheres. One variant of this process involves incorporating the dye or dye directly into the polymer organic solution. The rate of solvent removal by the extraction method depends on the temperature of the water, the ratio of the emulsion volume to the water, and the solubility profile of the polymer.

[00156] Semi-emulsion solvent diffusion. A novel quasi-emulsion solvent diffusion method for producing controlled release microspheres of drugs with acrylic polymers has been reported in the literature. The microparticles can be produced by a quasi-emulsion solvent diffusion method using an external phase containing distilled water and polyvinyl alcohol. The internal phase consists of dye / dye, ethanol and polymer. The concentration of the polymer is to increase plasticity. First, the internal phase is prepared at 60 ° C. and then added to the external phase at room temperature. After the emulsification process, the mixture is continuously stirred for 2 hours. The mixture can then be filtered to separate the microparticles. The product is then washed and dried in a vacuum oven at 40 ° C. for 1 day.

[00157] Polymerization technology. Polymerization techniques commonly used to prepare microspheres are mainly described below: Normal polymerization II. It is classified as interfacial polymerization. Both are done in the liquid phase.

[00158] I. Conventional Polymerization: Bulk, Suspension, Precipitation, Emulsion and Micelle Polymerization is performed by using different techniques. In bulk, the monomer or the combination of the monomer with the initiator or catalyst is usually heated to initiate polymerization. The polymer thus obtained can be molded as microspheres. Dye / dye loading can be done during the polymerization process. Suspension polymerization is also called bead or pearl polymerization. This is done by heating the monomer or composition of the monomer as a droplet dispersion in a continuous aqueous phase. The droplets may also contain initiators and other additives. Emulsion polymerization deviates from suspension polymerization due to the presence of the initiator in the aqueous phase, which then diffuses to the surface of the micelles. Bulk polymerization has the advantage of forming a pure polymer.

[00159] II. Interfacial polymerization: This involves the reaction of various monomers at the interface between the two immiscible liquids to form a film of polymer that essentially encloses the dispersed phase.

[00160] PH-triggered microparticles. Microparticles designed to emit their payload when exposed to acidic conditions are provided as a vehicle for dye / dye release. Any dye / dye can be encapsulated in a lipid-protein-sugar or polymer matrix with a PH trigger to form microparticles. Preferably, the diameter of the pH-triggered microparticles ranges from 50 nm to 10 micrometers. The matrix of particles can be prepared using any known lipid (eg, DPPC), protein (eg, albumin), or sugar (eg, lactose). The matrix of particles can also be prepared using any synthetic polymer such as polyester. The process of preparation involves providing the agent, contacting it with a PH triggering agent and a component selected from lipids, proteins and sugars, and spray drying the resulting mixture to produce microparticles. .. Typically, the PH triggering agent is a compound containing a polymer with a pKa of less than 7. PH-triggered microparticles release encapsulating dyes / dyes when exposed to an acidic environment.

[00161] Microfluidics. It has been reported that microfabrication using the microfluidic method synthesizes monodisperse microparticles. Average deviation of less than 5% by producing highly monodisperse emulsions of polymers and dye / dye droplets (easily controlled by the combination of the driving pressure of the two immiscible fluids and the shape of the microchannels). Microspheres containing a dye / dye having a diameter can be obtained with a high treatment amount.

[00162] Crosslinking / gelling. A sol-gel method or a gelation method is used for the production of fine particles. The gelling method uses a polymer solution containing a dye / dye and starts from a sol state (colloidal solution) that develops into a gel state (particles), which acts as a cross-linking agent for the polymer. It is extruded and submerged in the coagulation solution.

[00163] Electrohydrodynamic process or electrospray. Electrohydrodynamic processes or electrosprays are one-step techniques that have the potential to produce a narrow size distribution of submicrometric particles in high yields with limited particle agglutination. The principle of electrospray is based on the ability of the electric field to deform the interface of the droplet, established by Lord Rayleigh in 1882. The electrospray process is conceptually simple: a polymer solution is loaded into a syringe and injected at a constant rate through a small but highly charged capillary (eg, a 16-26 gauge needle) using a syringe pump. The applicable voltage used is typically up to + or -30 kV and the collector can be located at a distance of 7-30 cm from the capillary. As the droplet separates from the Taylor cone, the solvent evaporates, producing densely solid particles that are propelled towards the collector. In the context of dye / dye loading, the dye / dye is mixed with the polymer solution prior to electrospray. In addition, the size of the final product can be controlled by manipulating governing factors such as systems, solutions, equipment and ambient parameters. System parameters include the molecular weight and microstructural characteristics of the polymer. The type and concentration of polymer and solvent used determines the solution properties, ie pH, conductivity, viscosity and surface tension. Instrument parameters include the potential applied, the flow rate of the solution, the distance between the tip of the needle and the collector, and sometimes the properties of the collector material. In addition, ambient conditions such as temperature, humidity, and air velocity in the process chamber together determine the rate of evaporation of the solvent from the electrosprayed product.

[00164] Hot melt. This method has also been applied in the pharmaceutical field to prepare sustained release tablets and transdermal drug delivery systems. This method can also be applied in ink particle preparation. This technique uses low melting point polymers. The polymer is heated to a melting phase, then dispersed in a suitable dispersion medium containing the dye / dye, slowly cooled and processed into microspherical forms. Microspheres with SD of 1% to 5% have been reported.

[00165] Precision particle manufacturing technology (PPF technology). Precision Particle Manufacturing (PPF) is a technique developed to produce uniform particles of various materials and adapted for the production of emission controlled microparticle systems containing biodegradable polymers. The main device of PPF is to pass a fluid containing a sphere-forming material (ie, biodegradable polymer) and any dye / dye encapsulated through a small (10-100 μm) orifice to form a smooth cylindrical flow. Based on doing. To split the flow into uniform droplets, the nozzle is acoustically excited by a piezoelectric transducer driven by a wave generator at a defined frequency. The size and shape of the microparticles can be further controlled by using a non-solvent phase cyclic flow called carrier flow that surrounds the polymer-dye / dye jet to provide additional "traction" force. , It is possible to generate particles even smaller than the nozzle opening.

[00166] In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art from the above description. Such changes are also intended to be included within the appended claims. All references cited in this application, including, but not limited to, journal articles, US and non-US patents, patent application publications, international patent application publications, gene bank accession numbers, etc., are by reference in their entirety. Incorporated in the statement.

Example 1
Preparation of PLLA / PLGA particles using water-soluble colorants
[00167] The production of double-walled particles combines the phenomenon of phase separation of two polymers in an organic solvent when the critical concentration is reached and the process of solvent evaporation. The colorant-loaded particles utilize this modified oil-in-water (O / O / W) emulsion solvent evaporation technique to take advantage of the polymer incompatibility between PLLA and PLGA that results in complete total separation. Is prepared.

[00168] Prepare separate solutions of PLLA and PLGA (15-20%, w / v) in dichloromethane (DCM). A typical DCM volume used is 335 to 1000 μl. To prepare the PLGA polymer solution, prior to the addition of the polymer PLGA, a colorant is added to the DCM and sonicated at 2 W output for 30 seconds using an ultrasonic probe (model XL2000, Misonix, NY, USA) for coloring. It differs slightly in that it decomposes all crystals of the agent into smaller filaments (<20 μm). The two polymer solutions are then added together and sonicated at 2 W for 20 seconds to form an oil-in-oil (O / O) emulsion. This becomes clear when the initially transparent polymer solution becomes translucent, which looks milky white. Dropping the emulsion into a 200 ml PVA aqueous solution (2.5%, w / v) non-solvent produces an O / O / W emulsion.

[00169] Stirring with a mechanical stirrer at a rate of 250 rpm for 4 hours allows extraction and evaporation of the DCM as well as curing of the particles. Filtration, washing and lyophilization under vacuum follow. The particles produced are stored in a desiccator to prevent hydrolysis of the biodegradable polymer under moisture. Microspheres with various shell thicknesses and core diameters are prepared in the same manner by varying the polymer mass ratio (w / w) of PLLA and PLGA in the range 3: 1-1: 1. Single polymer (PLLA and PLGA) particles intended for characterization and baseline comparison are also prepared using well-established single emulsion methods commonly known in the art.

Both morphology of unloaded and colorant-loaded particles is studied with a scanning electron microscope, where surface and cross-sectional morphology and decomposition of the particles at various stages of in vitro emission are studied. The particles to be tested are first cross-sectioned using a microtome blade with a freeze-holding medium and placed on a metal stub with double-sided carbon tape. After the sample is air-dried, it is coated with a platinum layer using an autofine coater.

Observations with a light microscope are performed to identify different polymer layers in double-walled particles based on differences in crystal structure, and to identify the distribution of colorants in the loaded particles. In preparation for light microscopy, microspheres are sectioned using a microtome blade and placed on a glass slide for observation under cross-polaroid.

[00172] The particle size distribution and average particle size are determined using a Coulter laser diffraction particle size analyzer. The particles are suspended in ultrapure water and flowed through an analyzer.

[00173] To determine the composition of the core and shell polymers, the solubility difference between the polymer vs. PLLA and PLGA in ethyl acetate is utilized. PLGA is soluble, but PLLA is not. Double-walled particles are initially cross-sectioned approximately at the centerline. Each half is then individually immersed in a small amount of ethyl acetate and dissolved for about 10 minutes with little or no stirring. The cross-sectioned particle debris is then removed for optical observation. This solution is also tested to ensure that the core has not fallen off in any case. Therefore, two possible scenarios of hollow core or core residue can arise, depending on whether the core or shell melts. Optical microscopy of the cross section makes it possible to identify the remaining PLLA polymers as either shells or cores, and whether they are completely phase separated.

[00174] This method was used in conjunction with IR studies using Fourier Transform Infrared (FTIR) spectra obtained using an FTIR microscope connected to the FTIR spectrophotometer main frame, and was used with Bio-Rad analysis software in the medium IR range. The analysis is performed using a wave number of 400 to 4000 ^{cm -1} and a resolution of 2 cm ^-1). Standard particles of single polymer and double wall composite particles are cut in half and placed on a gold slide for testing. The software is used to randomly select 10 points in the core and shell to obtain a transmission spectrum. The average of these spectra is obtained and compared to the spectrum of a single polymer particle used as a reference for the analysis of the composition of each zone.

式中、Ｃ_実際（ｍｇ）は、粒子中に含まれる着色剤の実際の量であり、Ｃ_理論的（ｍｇ）は、最初に使用される着色剤の総量に等しい理論的装填量である。粒子中にカプセル化された着色剤の実際の量は、抽出法を用いて決定され、ここで、５ｍｇの微小球が３連で正確に秤量され、２ｍｌのＤＣＭ、クロロホルム又はジメチルスルホキシド（ＤＭＳＯ）の各々に溶解される。 [00175] Encapsulation efficiency is defined as the ratio of the actual load to the theoretical load of colorant in the particles, as described in the following equation:

In the formula, C _actual (mg) is the actual amount of colorant contained in the particles, and C _theoretical (mg) is the theoretical loading amount equal to the total amount of colorant initially used. The actual amount of colorant encapsulated in the particles was determined using an extraction method, where 5 mg microspheres were accurately weighed in triplets and 2 ml DCM, chloroform or dimethyl sulfoxide (DMSO). It is dissolved in each of.

[00176] Extraction of the colorant is carried out using 5 ml of deionized water to which the water-soluble colorant is preferentially distributed. The solution with the two immiscible phases is then centrifuged at 90.6 g for 10 minutes, then the top layer of water is extracted, any residual particles are filtered and high performance liquid chromatography (HPLC) is used. The colorant concentration is analyzed.

[00177] Colorant-loaded particles (5 ± 0.5 mg) are accurately weighed in triplets for release studies and placed in vials containing 1.8 ml PBS (pH 7.2). The vial is maintained at a physiological temperature of 37 ° C. in a thermostat vibrating water bath at 120 rpm. A 1.8 ml volume of aliquots is centrifuged at 90.6 g for 5 minutes, then collected at a preselected time and the vials are replaced with the same volume of freshly prepared PBS. The colorant content in the supernatant is analyzed using HPLC. The peak area obtained was compared to calibration to determine the colorant concentration and the percentage of colorant released at each calculated data point. A fresh amount of PBS is added to the particles and the removed supernatant is replaced.

Irradiation of the sample is ^{performed using a Gamma Chamber (60} Co. source, half-life 5.27 years) with doses of 50 Gy, 25 kGy applied to the sample at a dose rate of 2.5 Gy / h. .. Dry ice is added to the sample during the irradiation process to reduce the local temperature of the sample and prevent the sample from undergoing thermal decomposition. This is a common practice when high doses are used.

Thermal analysis of particles is performed using a modulated differential scanning calorimeter with a controller connected to the cooling system. Place the sample (about 6.5 mg) in a sealed aluminum dish, heat from -20 ° C to 200 ° C for the first heating lamp (ramp), all at a rate of 10 ° C / min, and cool to -10 ° C. , Reheat to 200 ° C with the second lamp. The obtained data is processed by TA universal analyzer software to identify the _{glass transition temperature (T g} ) and crystal melting point (T _m).

[00180] Decomposition studies are performed according to the following procedure: the loaded particles and blank particles (20 ± 5 mg) are each accurately weighed and placed in a vial containing 10 ml PBS buffer maintained at 120 rpm at 37 ° C. in a thermostatic vibrating water bath. put in. For extensive studies with SEM and DSC, microspheres are removed at pre-specified times. SEM studies are performed on the loaded microspheres to study the effect of polymer degradation on colorant release and the relationship between the physical properties of the polymer and the feature points of the release profile. Blank particles are for thermal DSC studies to characterize any changes in _{polymers T g} and T _{m under decomposition.}

Example 2
Preparation of POE / PLGA particles with water-soluble and insoluble colorants
[00181] Colorant-loaded double-walled polyorthoester / poly (lactide-co-glycolide) (POE / PLGA) particles with 50% POE by weight are evaporated into a water-in-water double emulsion solvent. Prepared by using the method. Briefly, 300 mg POE, 300 mg PLGA and 70 mg water-insoluble colorant (CA1) are dissolved in 12 ml DCM (organic phase); 70 mg water-soluble colorant (CA2) is 0.2% ( w / v) Dissolve in 0.15 ml of water containing PVA (internal aqueous phase). The two solutions are mixed and sonicated for 15 seconds to form a first water-in-oil emulsion. Then, the emulsion was poured into 250 ml of PBS (pH 7.4) (external aqueous phase) containing 0.2% (w / v) PVA as an emulsifier to form a water-in-water double emulsion. Using a mixer controlled by a low temperature circulator, stir at a constant temperature (15 ° C.) for 3.5 hours. The resulting particles are filtered, washed, lyophilized overnight and stored at 4 ° C.

[00182] Neat POE and PLGA particles containing CA1 or CA2 are prepared by the same method as described above. The internal aqueous phase is still used in the production of double-walled POE / PLGA particles loaded with CA1.

[00183] To measure CA2 encapsulation efficiency, 10 mg particles are dissolved in 1 ml DCM and held at room temperature for about 30 minutes. After dissolution of the particles, add 10 ml PBS buffer (pH 7.4) and shake the mixture vigorously for 2 minutes. After allowing this mixture to stand at room temperature for 1 hour, the aqueous layer is removed. The aqueous solution is then filtered. The CA2 content in the filtered solution is analyzed using high performance liquid chromatography (HPLC).

[00184] 5 mg particles are dissolved in 1 ml DCM to measure CA1 encapsulation efficiency. After dissolution of the particles, 5 ml of hexane is added to precipitate the polymer and CA1 is extracted. The mixture is filtered and the filtrate is dried. Add 20 ml volume of acetonitrile / water (85:15, v / v) to dissolve the solid sample. The CA1 content is analyzed by HPLC.

[00185] Colorant loading and encapsulation efficiency are calculated as the ratio of colorant to polymer content and the ratio of actual colorant content to theoretical colorant content, respectively.

[00186] The surface and internal morphology of the particles before and after in vitro decomposition in PBS at 37 ° C. are analyzed using a scanning electron microscope. Cross-sectioned samples are prepared using a razor blade to observe their internal structure. The particles and their cross-sectioned samples are placed on metal stubs using double-sided adhesive tape and vacuum coated with a platinum layer prior to testing.

[00187] Particle samples are incubated in PBS (pH 7.4) at 37 ° C. Water uptake of particles at predetermined time intervals is measured by weight measurement and calculated as the weight ratio of absorbed water to dry particles.

[00188] In vitro colorant release analysis of particles is performed in triplicate at 37 ° C. in PBS (pH 7.4). A 40 mg amount of lyophilized particles is dispersed in 10 ml PBS (pH 7.4) containing 0.1 (w / v)% Tween 80 and stirred appropriately. At predetermined time intervals, the in vitro medium is removed from each sample and replaced with fresh PBS buffer. For CA2-loaded particles, the CA2 content in the in vitro medium is analyzed directly using HPLC as described above. For CA1-loaded microspheres, an extraction method is used to separate the water-insoluble colorant from the in vitro medium. Briefly, 10 ml of hexane is added to the in vitro medium and the mixture is vibrated vigorously for 5 minutes to extract CA1. After allowing the mixture to stand overnight at room temperature, the organic layer is removed and dried. 5 ml volumes of acetonitrile / water (85:15, v / v) are then added to dissolve the residue for further HPLC analysis. CA1 standard samples are prepared according to the same procedure. However, for CA1-CA2-loaded microspheres, after extraction of CA1, an aqueous layer is collected to analyze the CA2 content. The weight percentage (%, w / w) of cumulative release of CA1 or CA2 is examined as a function of incubation time.

Example 3
In vitro decomposition of PLLA / P (CPP: SA) particles
[00189] Particles are prepared by solvent evaporation. For DW particles, 7 batches are prepared as follows and pooled before sieving. Prepare two solutions: 15% (w / v) PLLA in methylene chloride (4 ml) and 15% (w / v) P (CPP: SA) 20:80 in methylene chloride (4 ml). Two solutions. Mix briefly by shaking gently and pour into 600 ml of 0.5% PVA in distilled water. Stirring is performed at a speed of 450 rpm using an overhead stirrer (Caframo, Type RZR50). When the solvent evaporates, the polymer phase separates and the PLLA phase takes up the P (CPP: SA) 20:80 phase. The particles are stirred for 90-100 minutes, then collected by centrifugation, washed with distilled water, frozen and lyophilized. Sift them into a size range of about 100 μm and store at 20 ° C. The pooled particles are passed through a series of sieves and then collected at each stage. Particles with a diameter of 212-300 μm are used in the study.

[00190] SW PLLA particles are prepared in a similar manner and 8 batches are pooled. Particles are prepared from a 15% (w / v) solution in methylene chloride (8 ml) and emulsified in 600 ml 0.5% (w / v) PVA in distilled water by overhead stirring at a rate of 450 rpm. .. The SW particles are stirred for 60 to 70 minutes and then treated as described above. Particles of the same diameter (212-300 μm) as DW particles will be used in the study.

[00191] For in vitro testing, 50 mg aliquots of both SW and DW particles are suspended in 1 ml phosphate buffered saline (PBS). After 1, 3 days, 1 and 2 weeks, 1, 2, 4, and 6 months, the aliquots of each set of particles were washed with distilled water, frozen, lyophilized, and GPC, FTIR spectroscopy, DSC, And SEM characterization. At each sampling, the PBS solution is replaced with fresh PBS for the remaining samples.

[00192] SEM samples are lyophilized, placed on metal stubs, and cross-sectioned with a razor blade to observe the internal structure. The sample is then sputter-coated with a 50-100 Å gold-palladium layer (Polaron Instrument E5100) and observed using a Hitachi S-2700 scanning electron microscope at an acceleration voltage of 10 kV.

[00193] Samples for transmission FTIR spectroscopy are prepared by casting a diluted solution of the sample (1% w / v in chloroform) onto sodium chloride (NaCl) crystals. All spectra are obtained using a Perkin-Elmer model 1725x spectrometer and are manipulated using Infrared Data Manager software (Perkin-Elmer). The DSC sample (5-15 mg) is sealed in an aluminum sample dish (Perkin-Elmer Express). Thermal analysis of particles is performed using a model DSC 7 (Perkin-Elmer) equipped with a controller model TAC 7 / DX (Perkin-Elmer). After equilibration (1 minute) at 20 ° C, the sample is first heated to -20 to 200 ° C, cooled to -10 ° C, and finally reheated to 200 ° C, all at a rate of ^{10 ° C min-1.} conduct. The data from the first lamp is used in all cases. The Perkin-Elmer Thermal Analysis software is used to analyze the thermogram for the calculation of the glass transition temperature (T _g ), melting temperature (T _{m), and enthalpy change (ΔH).}

[00194] Polymer and particle molecular weights are estimated using a GPC system (Perkin-Elmer) consisting of an isocratic LC pump model 250, an LC column oven model 101, an LC-30 RI detector, and a 900 series interface. To. The sample is eluted in HPLC grade chloroform (Fisher Scientific) through a PL gel 5μ mixed column and a 5μm 50Å- ^{1 column connected in series at a flow rate of 1.0 ml-1 and a temperature of 40 ° C.} The molecular weight of the polymer is determined relative to the polystyrene standard (Polysciences, molecular weight of ^{1000-1,860,000 gmol -1 ) using the Turbochrom and TC *} SEC software programs (Perkin-Elmer) for analysis. The sample is filtered prior to injection to remove any insoluble particles present.

Example 4
In vivo degradation of PLLA / P (CPP: SA) particles
[00195] An aliquot of 30 mg particles is loaded into a glass vial, the vial is closed with cotton and packaged for cold cycle ethylene oxide sterilization (EtO). Three aliquots of particles are prepared for each rat, two are implanted intraquadriceps and one is subcutaneously implanted between the scapulas. Four rats are used at each time point to provide sufficient material for later extraction for polymer characterization. The time of study is 1 and 2 weeks, 1, 2, 4, and 6 months. DW PLLA and P (CPP: SA) 20:80 microspheres are transplanted into 4 rats per time point and 24 rats at 6 time points. A second set of 24 rats is transplanted with SW PLLA microspheres for comparison. Rats are anesthetized with a 60 mg kg- ¹ IP injection of pentobarbital sodium (Nembutal®). The transplant site is shaved and wiped first with alcohol and then with an iodinated solution.

[00196] Using sterilization techniques, a 1 cm long skin incision is made on the quadriceps. The incision is then continued intramuscularly. The particles are then carefully poured into the muscle incision and the fascia is closed with a simple interrupted suture of 5-0 Vicryl to secure the implant. The skin incision is closed with continuous subcutaneous sutures, also using 5-0 Vicryl. After transplanting the particles into both hind limbs, the rat is prone and a 1 cm incision is made through the skin between the scapulas. A small subcutaneous pocket is formed and particles are introduced into this site. The skin incision is closed with continuous subcutaneous sutures using 5-0 Vicryl. Rats are restored on a heating pad after surgery. NIH guidelines for the care and use of laboratory animals (NIH Publication # 85-23 Rev. 1985) are adhered to. At designated time points after transplantation, rats are sacrificed by _{IP and intracardiac Nembutal® overdose or CO 2 inhalation.}

[00197] The implant site is then explanted for analysis. One subcutaneous implant and one intramuscular implant from each group of rats are carefully excised with surrounding tissue for histological evaluation. These are placed in 4% (w / v) paraformaldehyde in PBS for 6-8 hours and then incubated overnight in 30% (w / v) sucrose in PBS. The immobilized sample is mounted in an embedding medium, frozen and then sectioned on a cryostat into 40 μm thick sections for microscopy. The remaining explant sample is pooled, frozen and lyophilized in preparation for polymer extraction. The dried tissue is ground using a mortar and pestle and chloroform is added. The slurry is filtered through a 0.2 μm PVDF syringe filter and chloroform is evaporated from the filtrate. The dried extracted polymer is then characterized by GPC, FTIR spectroscopy, and DSC. The original particles after production and after ethylene oxide sterilization are characterized by the same method.

Claims (52)

(I) Particles:
(A) Containing bioabsorbable and biodegradable polymers
The polymers are polycaprolectone (PCL), poly D-lactic acid (PDLA), poly L-lactic acid (PLLA), poly (lactic acid-co-glycolic acid), (PLGA), polyethylene glycol (PEG), polyethylene glycol-. With a shell comprising diacrylate (PEGDA), poly (sebasic acid anhydride) (poly (SA)), polyorthoesters, aliphatic polyanhydrides, aromatic polyanhydrides, or block polymers thereof.
(B) A core containing a colorant having a molecular weight of about 5 to about 10 × 10 ^{6 daltons,}
With particles containing
(Ii) With the carrier solution,
A composition comprising. The particles are about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 15 μm, about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about. The composition according to claim 1, which has a diameter of 5 μm, about 4 μm, about 3 μm, about 2 μm, about 1 μm, or about 0.5 μm or less. The composition according to claim 1, wherein the particles have a size that induces agglutination when incorporated into the dermis of an animal or human. The composition according to claim 1 or 2, wherein the polymer is present in the shell at a concentration effective to induce agglutination when incorporated into the dermis of an animal or human. The composition according to any one of claims 1 to 4, wherein the polymer is present in the particles in an amount sufficient to prevent or inhibit the phagocytosis of the colorant. The composition according to any one of claims 1 to 5, wherein the shell has a thickness of about 0.2 μm to 10 μm (including both ends). The composition according to any one of claims 1 to 6, wherein the polymer has a weight average molecular weight of 50 Da to 200 kDa (including both ends). The composition according to any one of claims 1 to 7, wherein the polymer is crystalline or semi-crystalline. The composition according to any one of claims 1 to 7, wherein the polymer is amorphous. The composition according to any one of claims 1 to 9, wherein the polymer is cationic at a physiological pH. The composition according to any one of claims 1 to 9, wherein the polymer is anionic at a physiological pH. The composition according to any one of claims 1 to 11, wherein the polymer undergoes surface erosion in an aqueous solution. The composition according to any one of claims 1 to 11, wherein the polymer undergoes bulk erosion in an aqueous solution. Claims 1-13, wherein the polymer, the weight average molecular weight, and the thickness of the shell are configured such that at least one of the bioabsorption profile and the biodegradation profile exhibits a delay step of about 2 months to about 12 months. The composition according to any one of the above. The composition according to any one of claims 1 to 14, wherein the shell further comprises a temperature responsive polymer. The composition according to any one of claims 1 to 15, wherein the colorant is a dye. The composition according to any one of claims 1 to 15, wherein the colorant is a dye. The composition according to any one of claims 1 to 15, wherein the colorant is fluorescent or phosphorescent. The composition according to any one of claims 1 to 18, wherein the colorant is present in the core in an amount of 1 ng to 1 μg (including both ends). The composition according to any one of claims 1 to 19, wherein the core comprises the colorant and the colorant is an aggregate. 20. Composition. The composition according to any one of claims 1 to 19, wherein the core further comprises a core polymer. 22. The composition of claim 22, wherein the polymer and the core polymer are the same. 22. The composition of claim 22, wherein the polymer and the core polymer are different. The composition according to any one of claims 22 to 24, wherein at least one of the polymer and the core polymer is the block copolymer, and the block copolymer comprises a diblock copolymer or a triblock copolymer. The core polymer is about 7% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35%. ~ 40%, about 40% ~ 45%, about 45% ~ 50%, about 50% ~ 55%, about 55% ~ 60%, about 60% ~ 65%, about 65% ~ 70%, about 70% ~ 22-25, claim 22-25, which are present in the particles at concentrations of 75%, about 75% -80%, about 80% -85%, about 85% -90%, or about 90% -92% w / w. The composition according to any one. The composition according to any one of claims 22 to 26, wherein the colorant is adsorbed on the core polymer, physically captured by the core polymer, or covalently bonded to the core polymer. thing. The composition according to any one of claims 22 to 26, wherein the colorant comprises a metal that forms a coordination bond with the core polymer. The composition according to any one of claims 22 to 27, wherein the colorant has a concentration of about 0.01% to 10% w / w (including both ends) based on the total polymer weight of the particles. thing. The composition according to any one of claims 1 to 19, wherein the core comprises a hydrogel. The colorant is adsorbed on the hydrogel, physically captured by the hydrogel, inserted into the hydrogel, non-covalently attached to the hydrogel, or covalently attached to the hydrogel. , The composition according to claim 30. The hydrogel is at least one of alginate, chitosan hydrochloride, methacrylate-modified hyaluronic acid (HA-MA), thiolated hyaluronic acid (HA-SH), poly (N-isopropylacrylamide) (PNIPAM), and polyethylene glycol (PEG). The composition according to claim 30 or 31, comprising one. The composition according to claim 30 or 31, wherein the colorant comprises a metal that forms a coordination bond with the hydrogel. The cores are alginate, pectin, chitosan, hyaluronic acid, κ-carrageenan, agarose, agar, cellulose derivatives, carboxymethyl cellulose (CMC), protein-based hydrophilic polymers, collagen hydrolysates, gelatin, synthetic hydrophilic polymers, poly. The composition according to any one of claims 1-19 or 22-33, further comprising at least one of acrylamide, polyacrylic acid, polyvinyl alcohol, polyethylene glycol (PEG) and modified PEG. The shell or core is poly [bis (p-carboxyphenoxy) methane] (poly (CPM)), poly [1,3-bis (p-carboxyphenoxy) propane] poly (CPP), poly [1,6. -Bis (p-carboxyphenoxy) hexane] (poly (CPH)), poly (anhydrous sebacic acid) (poly (SA)), poly [1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate], And poly [1,4-bis (hydroxyethyl) terephthalate-alt-ethyloxyphosphate-co-1,4-bis (hydroxyethyl) terephthalate-co-terephthalate (P (BHET-EOP / BHET), 80/20)) The composition according to any one of claims 1-19 or 22-34, further comprising at least one polyanhydride selected from the group consisting of. Any of claims 1-19 or 22-35, wherein the shell or core further comprises at least one polyorthoester (POE) selected from the group consisting of POE I, POE II, POE III, and POE IV. The composition described in Crab. The particles are about 5 mg / ml to about 20 mg / ml, about 20 to about 50, about 50 to about 80, about 80 to about 110, about 110 to about 140, about 140 to about 170, about 170 to about 200, About 200 to about 230, about 230 to about 250, about 250 to about 280, about 280 to about 310, about 310 to about 340, about 340 to about 370, about 370 to about 400, about 400 to about 430, about 430. ~ 450, about 450 to about 480, about 480 to about 510, about 510 to about 540, about 540 to about 570, about 570 to about 600 mg / ml, or 80 mg / ml to about 800 mg / ml. The composition according to any one of claims 1 to 36, which is present in the solution. The particles are about 5% to about 8%, about 8% to about 11%, about 11% to about 14%, about 14 to about 17, about 17 to about 20, about 20 to about 23, about 23 to about. 25, about 25 to about 28, about 28 to about 31, about 31 to about 34, about 34 to about 37, about 37 to about 40, about 37 to about 40, about 40 to about 43, about 43 to about 45, About 45 to about 48, about 48 to about 50, about 50 to about 53, about 53 to about 55, about 55 to about 58, about 58 to about 60%, about 5% to about 80% w / v, about 10 % To about 80% w / v, about 15% to about 80% w / v, about 20% to about 80% w / v, about 25% to about 80% w / v, about 30% to about 80% w / V, about 35% to about 80% w / v, about 40% to about 80% w / v, about 45% to about 80% w / v, about 50% to about 80% w / v or about 60% The composition according to any one of claims 1 to 36, which is present in the carrier solution at a concentration of about 80% w / v. The composition according to any one of claims 1 to 38, wherein the composition has a concentration sufficient to maintain the osmotic pressure in the particles for at least about 2 months to about 60 months. The composition according to any one of claims 1 to 39, further comprising a moisturizer. The composition according to any one of claims 1 to 40, further comprising a biocide. The composition according to any one of claims 1 to 41, further comprising a buffer. The composition according to any one of claims 1-42, further comprising a temperature-responsive polymer. 43. The composition of claim 43, wherein one of the temperature-responsive polymers is poly (N-isopropylacrylamide) (PNIPAM). The composition according to any one of claims 1 to 44, further comprising a surfactant. The composition of claim 45, wherein the surfactant comprises a copolymer. 15. The composition of claim 15, wherein the temperature-responsive polymer is poly (N-isopropylacrylamide) (PNIPAM). The block polymers are poly (bis (p-carboxyphenoxy) methane (poly (CPM)) and poly (sebacic anhydride) (poly (SA)), poly (1,3-bis (p-carboxyphenoxy) propane). (Poly (CPP)) and poly (sebacic acid anhydride) (poly (SA)), poly (1,4-bis (p-carboxyphenoxy) butane (poly (CPB)) and poly (sebacic acid anhydride) (poly (poly) SA)), or a diblock polymer comprising a combination of poly (1,6-bis (p-carboxyphenoxy) hexane (poly (CPH)) and poly (sebacic anhydride) (poly (SA))). 25. The composition according to 25. A method of tattooing a subject, comprising administering to the subject the composition according to any one of claims 1-48. 49. The method of claim 49, wherein the administration step comprises intradermal administration of the composition according to any one of claims 1-48 of a cosmetically effective amount. A method of inhibiting the absorption of a colorant in the skin of a subject, comprising encapsulating the colorant in the particles of any one of claims 1-48. A method of treating a pigment disorder in a subject in need of treatment of the pigment disorder, comprising contacting the subject's skin with the particles of any one of claims 1-48 of a therapeutically effective dose. Method.

Images